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Christmas: A Time for Love and... Penile Fractures
A power outage, like the 1977 blackout in New York City, can lead to an increase in violent crime. However, complete darkness can also have an upside, as it can encourage intimacy and subsequently boost birth rates. The Christmas season, sometimes called the festival of love, appears to stimulate human interactions. Yet this, also, has its downsides, as recently reported by Dr. Nikolaos Pyrgidis and other urologists at Ludwig Maximilian University of Munich in Germany.
The team found that the Christmas period, in particular, is that bit more risky for this injury after they evaluated data from about 3400 men (average age 42) treated for penile fractures between 2005 and 2021. The data was provided by Germany’s Federal Bureau of Statistics.
Out of the 3400 penile fractures that were reported during this period, 40 (1.2%) occurred over 51 Christmas days (from 24th to 26th December each year). The daily incidence rate of penile fractures during the Christmas period was 0.78, with an incidence rate ratio (IRR) of 1.43. The authors note that, if every day were like Christmas, there would have been a 43% increase in penile fractures in Germany since 2005. Interestingly, only 28 (0.82%) penile fractures were reported during the New Year (from 31 December to 2 January in the period between 2005 and 2021), with an IRR of 0.98.
More generally, most patients with penile fractures were admitted to the hospital over the weekend (n=1322; IRR 1.58). Notably, Sunday saw the most admissions due to this injury, followed by Saturday. This suggests that men engaging in sexual activities on Saturday night bear the highest risk of penile fractures, followed by those active on Friday nights.
Penile fractures also increased in the summer months (n=929; IRR 1.11). But the COVID-19 pandemic (n=385; IRR 1.06) and the lockdowns (n=93; IRR 1.95%) did not impact the frequency of this injury.
Rare, Painful, and an Emergency
Penile fractures are a rare urological emergency. The tunica albuginea of one or both corpora cavernosa must tear to be considered problematic, as another team of authors reported in a recent publication. Involvement of the urethra and corpus spongiosum is also possible.
Injuries often occur during an erection because it makes the tunica albuginea stiffer and thinner than when the penis is flaccid. Patients report hearing a snap when the penis is forced into an angle during sexual activity. This was reportedly the case with German singer-song writer Dieter Bohlen, whose ex-girlfriend Nadja Abd El Farrag is said to have written in her book “Ungelogen”, or “Honestly”, that there was a sudden snap during an intimate moment one December night (Christmas?), after which she called the fire brigade in her distress.
Multiple Causes Possible
Other factors contributing to penile fractures include rolling over in bed onto an erect penis, forced bending to achieve detumescence, and blunt external traumas like kicks.
Some penile fractures can be caused by patients “kneading and ripping” their erect penis to quickly reduce swelling. In an Iranian study, 269 out of 352 patients (76%) who underwent this process, known as “ taqaandan” in Iran, suffered a penile fracture.
Penile fractures can also occur in children, as evidenced by the case history of a 7-year-old boy described a few years ago in the journal Urology where the cause was a fall onto the penis.
Immediate Action Required
The treatment of choice for a fresh penile fracture is surgical repair of the tunica albuginea defect and, if necessary, the urethra. Timely surgical intervention yields significantly better long-term outcomes than conservative therapy regarding late complications such as erectile dysfunction and penile curvature. It also reduces the rate of early complications, such as severe corporal infections. Conservative therapy should be reserved for patients who explicitly refuse surgical intervention after thorough consultation.
This article was translated from Univadis Germany using ChatGPT followed by human editing.
A version of this article appeared on Medscape.com.
A power outage, like the 1977 blackout in New York City, can lead to an increase in violent crime. However, complete darkness can also have an upside, as it can encourage intimacy and subsequently boost birth rates. The Christmas season, sometimes called the festival of love, appears to stimulate human interactions. Yet this, also, has its downsides, as recently reported by Dr. Nikolaos Pyrgidis and other urologists at Ludwig Maximilian University of Munich in Germany.
The team found that the Christmas period, in particular, is that bit more risky for this injury after they evaluated data from about 3400 men (average age 42) treated for penile fractures between 2005 and 2021. The data was provided by Germany’s Federal Bureau of Statistics.
Out of the 3400 penile fractures that were reported during this period, 40 (1.2%) occurred over 51 Christmas days (from 24th to 26th December each year). The daily incidence rate of penile fractures during the Christmas period was 0.78, with an incidence rate ratio (IRR) of 1.43. The authors note that, if every day were like Christmas, there would have been a 43% increase in penile fractures in Germany since 2005. Interestingly, only 28 (0.82%) penile fractures were reported during the New Year (from 31 December to 2 January in the period between 2005 and 2021), with an IRR of 0.98.
More generally, most patients with penile fractures were admitted to the hospital over the weekend (n=1322; IRR 1.58). Notably, Sunday saw the most admissions due to this injury, followed by Saturday. This suggests that men engaging in sexual activities on Saturday night bear the highest risk of penile fractures, followed by those active on Friday nights.
Penile fractures also increased in the summer months (n=929; IRR 1.11). But the COVID-19 pandemic (n=385; IRR 1.06) and the lockdowns (n=93; IRR 1.95%) did not impact the frequency of this injury.
Rare, Painful, and an Emergency
Penile fractures are a rare urological emergency. The tunica albuginea of one or both corpora cavernosa must tear to be considered problematic, as another team of authors reported in a recent publication. Involvement of the urethra and corpus spongiosum is also possible.
Injuries often occur during an erection because it makes the tunica albuginea stiffer and thinner than when the penis is flaccid. Patients report hearing a snap when the penis is forced into an angle during sexual activity. This was reportedly the case with German singer-song writer Dieter Bohlen, whose ex-girlfriend Nadja Abd El Farrag is said to have written in her book “Ungelogen”, or “Honestly”, that there was a sudden snap during an intimate moment one December night (Christmas?), after which she called the fire brigade in her distress.
Multiple Causes Possible
Other factors contributing to penile fractures include rolling over in bed onto an erect penis, forced bending to achieve detumescence, and blunt external traumas like kicks.
Some penile fractures can be caused by patients “kneading and ripping” their erect penis to quickly reduce swelling. In an Iranian study, 269 out of 352 patients (76%) who underwent this process, known as “ taqaandan” in Iran, suffered a penile fracture.
Penile fractures can also occur in children, as evidenced by the case history of a 7-year-old boy described a few years ago in the journal Urology where the cause was a fall onto the penis.
Immediate Action Required
The treatment of choice for a fresh penile fracture is surgical repair of the tunica albuginea defect and, if necessary, the urethra. Timely surgical intervention yields significantly better long-term outcomes than conservative therapy regarding late complications such as erectile dysfunction and penile curvature. It also reduces the rate of early complications, such as severe corporal infections. Conservative therapy should be reserved for patients who explicitly refuse surgical intervention after thorough consultation.
This article was translated from Univadis Germany using ChatGPT followed by human editing.
A version of this article appeared on Medscape.com.
A power outage, like the 1977 blackout in New York City, can lead to an increase in violent crime. However, complete darkness can also have an upside, as it can encourage intimacy and subsequently boost birth rates. The Christmas season, sometimes called the festival of love, appears to stimulate human interactions. Yet this, also, has its downsides, as recently reported by Dr. Nikolaos Pyrgidis and other urologists at Ludwig Maximilian University of Munich in Germany.
The team found that the Christmas period, in particular, is that bit more risky for this injury after they evaluated data from about 3400 men (average age 42) treated for penile fractures between 2005 and 2021. The data was provided by Germany’s Federal Bureau of Statistics.
Out of the 3400 penile fractures that were reported during this period, 40 (1.2%) occurred over 51 Christmas days (from 24th to 26th December each year). The daily incidence rate of penile fractures during the Christmas period was 0.78, with an incidence rate ratio (IRR) of 1.43. The authors note that, if every day were like Christmas, there would have been a 43% increase in penile fractures in Germany since 2005. Interestingly, only 28 (0.82%) penile fractures were reported during the New Year (from 31 December to 2 January in the period between 2005 and 2021), with an IRR of 0.98.
More generally, most patients with penile fractures were admitted to the hospital over the weekend (n=1322; IRR 1.58). Notably, Sunday saw the most admissions due to this injury, followed by Saturday. This suggests that men engaging in sexual activities on Saturday night bear the highest risk of penile fractures, followed by those active on Friday nights.
Penile fractures also increased in the summer months (n=929; IRR 1.11). But the COVID-19 pandemic (n=385; IRR 1.06) and the lockdowns (n=93; IRR 1.95%) did not impact the frequency of this injury.
Rare, Painful, and an Emergency
Penile fractures are a rare urological emergency. The tunica albuginea of one or both corpora cavernosa must tear to be considered problematic, as another team of authors reported in a recent publication. Involvement of the urethra and corpus spongiosum is also possible.
Injuries often occur during an erection because it makes the tunica albuginea stiffer and thinner than when the penis is flaccid. Patients report hearing a snap when the penis is forced into an angle during sexual activity. This was reportedly the case with German singer-song writer Dieter Bohlen, whose ex-girlfriend Nadja Abd El Farrag is said to have written in her book “Ungelogen”, or “Honestly”, that there was a sudden snap during an intimate moment one December night (Christmas?), after which she called the fire brigade in her distress.
Multiple Causes Possible
Other factors contributing to penile fractures include rolling over in bed onto an erect penis, forced bending to achieve detumescence, and blunt external traumas like kicks.
Some penile fractures can be caused by patients “kneading and ripping” their erect penis to quickly reduce swelling. In an Iranian study, 269 out of 352 patients (76%) who underwent this process, known as “ taqaandan” in Iran, suffered a penile fracture.
Penile fractures can also occur in children, as evidenced by the case history of a 7-year-old boy described a few years ago in the journal Urology where the cause was a fall onto the penis.
Immediate Action Required
The treatment of choice for a fresh penile fracture is surgical repair of the tunica albuginea defect and, if necessary, the urethra. Timely surgical intervention yields significantly better long-term outcomes than conservative therapy regarding late complications such as erectile dysfunction and penile curvature. It also reduces the rate of early complications, such as severe corporal infections. Conservative therapy should be reserved for patients who explicitly refuse surgical intervention after thorough consultation.
This article was translated from Univadis Germany using ChatGPT followed by human editing.
A version of this article appeared on Medscape.com.
Spending the Holidays With GLP-1 Receptor Agonists: 5 Things to Know
As an endocrinologist, I treat many patients who have diabetes, obesity, or both. Antiobesity medications, particularly the class of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), are our first support tools when nutrition and physical activity aren’t enough.
1. Be mindful of fullness cues.
GLP-1 RAs increase satiety; they help patients feel fuller sooner within a meal and longer in between meals. This means consuming the “usual” at a holiday gathering makes them feel as if they ate too much, and often this will result in more side effects, such as nausea and reflux.
Patient tip: A good rule of thumb is to anticipate feeling full with half of your usual portion. Start with half a plate and reassess your hunger level after finishing.
2. Distinguish between hunger and “food noise.”
Ask your patients, “Do you ever find yourself eating even when you’re not hungry?” Many people eat because of emotions (eg, stress, anxiety, happiness), social situations, or cultural expectations. This type of food consumption is what scientists call “hedonic food intake” and may be driven by the “food noise” that patients describe as persistent thoughts about food in the absence of physiologic hunger. Semaglutide (Ozempic, Wegovy) has been found to reduce cravings, though other research has shown that emotional eating may blunt the effect of GLP-1 RAs.
Patient tip: Recognize when you might be seeking food for reasons other than hunger, and try a different way to address the cue (eg, chat with a friend or family member, go for a walk).
3. Be careful with alcohol.
GLP-1 RAs are being researched as potential treatments for alcohol use disorder. Many patients report less interest in alcohol and a lower tolerance to alcohol when they are taking a GLP-1 RA. Additionally, GLP-1 RAs may be a risk factor for pancreatitis, which can be caused by consuming too much alcohol.
Patient tip: The standard recommendation remains true: If drinking alcohol, limit to one to two servings per day, but also know that reduced intake or interest is normal when taking a GLP-1 RA.
4. Be aware of sickness vs side effects.
With holiday travel and the winter season, it is common for people to catch a cold or a stomach bug. Symptoms of common illnesses might include fatigue, loss of appetite, or diarrhea. These symptoms overlap with side effects of antiobesity medications like semaglutide and tirzepatide.
Patient tip: If you are experiencing constitutional or gastrointestinal symptoms due to illness, speak with your board-certified obesity medicine doctor, who may recommend a temporary medication adjustment to avoid excess side effects.
5. Stay strong against weight stigma.
The holiday season can be a stressful time, especially as patients are reconnecting with people who have not been a part of their health or weight loss journey. Unfortunately, weight bias and weight stigma remain rampant. Many people don’t understand the biology of obesity and refuse to accept the necessity of medical treatment. They may be surrounded by opinions, often louder and less informed.
Patient tip: Remember that obesity is a medical disease. Tell your nosy cousin that it’s a private health matter and that your decisions are your own.
Dr. Tchang is Assistant Professor, Clinical Medicine, Division of Endocrinology, Diabetes, and Metabolism, Weill Cornell Medicine; Physician, Department of Medicine, Iris Cantor Women’s Health Center, Comprehensive Weight Control Center, New York, NY. She disclosed financial relationships with Gelesis and Novo Nordisk.
A version of this article appeared on Medscape.com.
As an endocrinologist, I treat many patients who have diabetes, obesity, or both. Antiobesity medications, particularly the class of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), are our first support tools when nutrition and physical activity aren’t enough.
1. Be mindful of fullness cues.
GLP-1 RAs increase satiety; they help patients feel fuller sooner within a meal and longer in between meals. This means consuming the “usual” at a holiday gathering makes them feel as if they ate too much, and often this will result in more side effects, such as nausea and reflux.
Patient tip: A good rule of thumb is to anticipate feeling full with half of your usual portion. Start with half a plate and reassess your hunger level after finishing.
2. Distinguish between hunger and “food noise.”
Ask your patients, “Do you ever find yourself eating even when you’re not hungry?” Many people eat because of emotions (eg, stress, anxiety, happiness), social situations, or cultural expectations. This type of food consumption is what scientists call “hedonic food intake” and may be driven by the “food noise” that patients describe as persistent thoughts about food in the absence of physiologic hunger. Semaglutide (Ozempic, Wegovy) has been found to reduce cravings, though other research has shown that emotional eating may blunt the effect of GLP-1 RAs.
Patient tip: Recognize when you might be seeking food for reasons other than hunger, and try a different way to address the cue (eg, chat with a friend or family member, go for a walk).
3. Be careful with alcohol.
GLP-1 RAs are being researched as potential treatments for alcohol use disorder. Many patients report less interest in alcohol and a lower tolerance to alcohol when they are taking a GLP-1 RA. Additionally, GLP-1 RAs may be a risk factor for pancreatitis, which can be caused by consuming too much alcohol.
Patient tip: The standard recommendation remains true: If drinking alcohol, limit to one to two servings per day, but also know that reduced intake or interest is normal when taking a GLP-1 RA.
4. Be aware of sickness vs side effects.
With holiday travel and the winter season, it is common for people to catch a cold or a stomach bug. Symptoms of common illnesses might include fatigue, loss of appetite, or diarrhea. These symptoms overlap with side effects of antiobesity medications like semaglutide and tirzepatide.
Patient tip: If you are experiencing constitutional or gastrointestinal symptoms due to illness, speak with your board-certified obesity medicine doctor, who may recommend a temporary medication adjustment to avoid excess side effects.
5. Stay strong against weight stigma.
The holiday season can be a stressful time, especially as patients are reconnecting with people who have not been a part of their health or weight loss journey. Unfortunately, weight bias and weight stigma remain rampant. Many people don’t understand the biology of obesity and refuse to accept the necessity of medical treatment. They may be surrounded by opinions, often louder and less informed.
Patient tip: Remember that obesity is a medical disease. Tell your nosy cousin that it’s a private health matter and that your decisions are your own.
Dr. Tchang is Assistant Professor, Clinical Medicine, Division of Endocrinology, Diabetes, and Metabolism, Weill Cornell Medicine; Physician, Department of Medicine, Iris Cantor Women’s Health Center, Comprehensive Weight Control Center, New York, NY. She disclosed financial relationships with Gelesis and Novo Nordisk.
A version of this article appeared on Medscape.com.
As an endocrinologist, I treat many patients who have diabetes, obesity, or both. Antiobesity medications, particularly the class of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), are our first support tools when nutrition and physical activity aren’t enough.
1. Be mindful of fullness cues.
GLP-1 RAs increase satiety; they help patients feel fuller sooner within a meal and longer in between meals. This means consuming the “usual” at a holiday gathering makes them feel as if they ate too much, and often this will result in more side effects, such as nausea and reflux.
Patient tip: A good rule of thumb is to anticipate feeling full with half of your usual portion. Start with half a plate and reassess your hunger level after finishing.
2. Distinguish between hunger and “food noise.”
Ask your patients, “Do you ever find yourself eating even when you’re not hungry?” Many people eat because of emotions (eg, stress, anxiety, happiness), social situations, or cultural expectations. This type of food consumption is what scientists call “hedonic food intake” and may be driven by the “food noise” that patients describe as persistent thoughts about food in the absence of physiologic hunger. Semaglutide (Ozempic, Wegovy) has been found to reduce cravings, though other research has shown that emotional eating may blunt the effect of GLP-1 RAs.
Patient tip: Recognize when you might be seeking food for reasons other than hunger, and try a different way to address the cue (eg, chat with a friend or family member, go for a walk).
3. Be careful with alcohol.
GLP-1 RAs are being researched as potential treatments for alcohol use disorder. Many patients report less interest in alcohol and a lower tolerance to alcohol when they are taking a GLP-1 RA. Additionally, GLP-1 RAs may be a risk factor for pancreatitis, which can be caused by consuming too much alcohol.
Patient tip: The standard recommendation remains true: If drinking alcohol, limit to one to two servings per day, but also know that reduced intake or interest is normal when taking a GLP-1 RA.
4. Be aware of sickness vs side effects.
With holiday travel and the winter season, it is common for people to catch a cold or a stomach bug. Symptoms of common illnesses might include fatigue, loss of appetite, or diarrhea. These symptoms overlap with side effects of antiobesity medications like semaglutide and tirzepatide.
Patient tip: If you are experiencing constitutional or gastrointestinal symptoms due to illness, speak with your board-certified obesity medicine doctor, who may recommend a temporary medication adjustment to avoid excess side effects.
5. Stay strong against weight stigma.
The holiday season can be a stressful time, especially as patients are reconnecting with people who have not been a part of their health or weight loss journey. Unfortunately, weight bias and weight stigma remain rampant. Many people don’t understand the biology of obesity and refuse to accept the necessity of medical treatment. They may be surrounded by opinions, often louder and less informed.
Patient tip: Remember that obesity is a medical disease. Tell your nosy cousin that it’s a private health matter and that your decisions are your own.
Dr. Tchang is Assistant Professor, Clinical Medicine, Division of Endocrinology, Diabetes, and Metabolism, Weill Cornell Medicine; Physician, Department of Medicine, Iris Cantor Women’s Health Center, Comprehensive Weight Control Center, New York, NY. She disclosed financial relationships with Gelesis and Novo Nordisk.
A version of this article appeared on Medscape.com.
A New Test Could Save Arthritis Patients Time, Money, and Pain. But Will It Be Used?
Erinn Maury, MD, knew Remicade wasn’t the right drug for Patti Schulte, a patient with rheumatoid arthritis the physician saw at her Millersville, Maryland, practice. Schulte’s swollen, painful joints hadn’t responded to Enbrel or Humira, two drugs in the same class.
But the insurer insisted, so Schulte went on Remicade. It didn’t work either.
What’s more, Schulte suffered a severe allergic reaction to the infusion therapy, requiring a heavy dose of prednisone, a steroid with grave side effects if used at high doses for too long.
After 18 months, her insurer finally approved Maury’s drug of choice, Orencia. By then, Schulte’s vertebrae, weakened by prednisone, had started cracking. She was only 60.
It’s also a story of how doctors are steered by pharmacy benefit managers — the middlemen of the drug market — as well as by insurers.
Once people with inflammatory conditions such as rheumatoid arthritis reach a certain stage, the first prescription offered is typically Humira, the best-selling drug in history, and part of a class known as tumor necrosis factor inhibitors, or TNFis, which fail to significantly help about half of the patients who take it.
“We practice rheumatology without any help,” said Vibeke Strand, a rheumatologist and adjunct clinical professor at Stanford. She bemoaned the lack of tools available to choose the right drug while bristling at corporate intervention in the decision. “We are told by the insurer what to prescribe to the patient. After they fail methotrexate, it’s a TNF inhibitor, almost always Humira. And that’s not OK.”
If there’s a shred of hope in this story, it’s that a blood test, PrismRA, may herald an era of improved care for patients with rheumatoid arthritis and other autoimmune conditions. But first, it must be embraced by insurers.
PrismRA employs a predictive model that combines clinical factors, blood tests, and 19 gene patterns to identify the roughly 60% of patients who are very unlikely to respond to a TNFi drug.
Over the past 25 years, drug companies have introduced five new classes of autoimmune drugs. TNFis were the first to market, starting in the late 1990s.
Some 1.3 million Americans have rheumatoid arthritis, a disease in which a person’s immune system attacks their joints, causing crippling pain and, if improperly treated, disfigurement. The newer drugs, mostly so-called biologics, are also used by some of the 25 million or more Americans with other autoimmune diseases, such as lupus, Crohn’s disease, and psoriasis. Typically costing tens of thousands of dollars annually, the drugs are prescribed after a patient fails to respond to older, cheaper drugs like methotrexate.
Until recently, rheumatologists have had few ways to predict which of the new drugs would work best on which patients. Often, “it’s a coin flip whether I prescribe drug A or B,” said Jeffrey Curtis, MD, a rheumatology professor at the University of Alabama-Birmingham.
Yet about 90% of the patients who are given one of these advanced drugs start on a TNFi, although there’s often no reason to think a TNFi will work better than another type.
Under these puzzling circumstances, it’s often the insurer rather than the doctor who chooses the patient’s drug. Insurers lean toward TNFis such as adalimumab, commonly sold as brand name Humira, in part because they get large rebates from manufacturers for using them. Although the size of such payments is a trade secret, AbbVie is said to be offering rebates to insurers of up to 60% of Humira’s price. That has enabled it to control 98.5% of the US adalimumab market, even though it has eight biosimilar competitors.
PrismRA’s developer, Scipher Medicine, has provided more than 26,000 test results, rarely covered by insurance. But on October 15, the Centers for Medicare & Medicaid began reimbursing for the test, and its use is expected to rise. At least two other companies are developing drug-matching tests for patients with rheumatoid arthritis.
Although critics say PrismRA is not always useful, it is likely to be the first in a series of diagnostics anticipated over the next decade that could reduce the time that patients with autoimmune disease suffer on the wrong drug.
Academics, small biotechs, and large pharmaceutical companies are investing in methods to distinguish the biological pathways involved in these diseases and the best way to treat each one. This approach, called precision medicine, has existed for years in cancer medicine, in which it’s routine to test the genetics of patients’ tumors to determine the appropriate drug treatment.
“You wouldn’t give Herceptin to a breast cancer patient without knowing whether her tumor was HER2-positive,” said Costantino Pitzalis, MD, a rheumatology professor at the William Harvey Research Institute in London, England. He was speaking before a well-attended session at an American College of Rheumatology conference in San Diego in November. “Why do we not use biopsies or seek molecular markers in rheumatoid arthritis?”
It’s not only patients and doctors who have a stake in which drugs work best for a given person.
When Remicade failed and Schulte waited for the insurer to approve Orencia, she insisted on keeping her job as an accountant. But as her prednisone-related spinal problems worsened, Schulte was forced to retire, go on Medicaid, and seek disability, something she had always sworn to avoid.
Now taxpayers, rather than the insurer, are covering Schulte’s medical bills, Dr. Maury noted.
Precision medicine hasn’t seemed like a priority for large makers of autoimmune drugs, which presumably have some knowledge of which patients are most likely to benefit from their drugs, because they have tested and sold millions of doses over the years. By offering rebate incentives to insurers, companies like AbbVie, which makes Humira, can guarantee theirs are the drugs of choice with insurers.
“If you were AbbVie,” Dr. Curtis said, “why would you ever want to publish data showing who’s not going to do well on your drug, if, in the absence of the test, everyone will start with your drug first?”
What Testing Could Do
Medicare and commercial insurers haven’t yet set a price for PrismRA, but it could save insurers thousands of dollars a year for each patient it helps, according to Krishna Patel, PharmD, Scipher’s associate director of medical affairs.
“If the test cost $750, I still only need it once, and it costs less than a month of whatever drug is not going to work very well for you,” said Dr. Curtis, a coauthor of some studies of the test. “The economics of a biomarker that’s anything but worthless is pretty favorable because our biologics and targeted drugs are so expensive.”
Patients are enthusiastic about the test because so many have had to take TNFis that didn’t work. Many insurers require patients to try a second TNFi and sometimes a third.
Jen Weaver, a patient advocate and mother of three, got little benefit from hydroxychloroquine, sulfasalazine, methotrexate, and Orencia, a non-TNFi biologic therapy, before finding some relief in another, Actemra. But she was taken off that drug when her white blood cells plunged, and the next three drugs she tried — all TNFis — caused allergic reactions, culminating with an outbreak of pus-filled sores. Another drug, Otezla, eventually seemed to help heal the sores, and she’s been stable on it since in combination with methotrexate, Ms. Weaver said.
“What is needed is to substantially shorten this trial-and-error period for patients,” said Shilpa Venkatachalam, PhD, herself a patient and the director of research operations at the Global Healthy Living Foundation. “There’s a lot of anxiety and frustration, weeks in pain wondering whether a drug is going to work for you and what to do if it doesn’t.” A survey by her group found that 91% of patients worried their medications would stop working. And there is evidence that the longer it takes to resolve arthritis symptoms, the less chance they will ever stop.
How insurers will respond to the availability of tests isn’t clear, partly because the arrival of new biosimilar drugs — essentially generic versions — is making TNFis cheaper for insurance plans. While Humira still dominates, AbbVie has increased rebates to insurers, in effect lowering its cost. Lower prices make the PrismRA test less appealing to insurers because widespread use of the test could cut TNFi prescriptions by up to a third.
However, rheumatologist John B. Boone, MD, in Louisville, Kentucky, found to his surprise that insurers mostly accepted alternative prescriptions for 41 patients whom the test showed unlikely to respond to TNFis as part of a clinical trial. Dr. Boone receives consulting fees from Scipher.
Although the test didn’t guarantee good outcomes, he said, the few patients given TNFis despite the test results almost all did poorly on that regimen.
Scientists from AbbVie, which makes several rheumatology drugs in addition to Humira, presented a study at the San Diego conference examining biomarkers that might show which patients would respond to Rinvoq, a new immune-suppressing drug in a class known as the JAK inhibitors. When asked about its use of precision medicine, AbbVie declined to comment.
Over two decades, Humira has been a blockbuster drug for AbbVie. The company sold more than $3.5 billion worth of Humira in the third quarter of 2023, 36% less than a year ago. Sales of Rinvoq, which AbbVie is marketing as a treatment for patients failed by Humira and its class, jumped 60% to $1.1 billion.
What Patients Want
Shannan O’Hara-Levi, a 38-year-old in Monroe, New York, has been on scores of drugs and supplements since being diagnosed with juvenile arthritis at age 3. She’s been nauseated, fatigued, and short of breath and has suffered allergic reactions, but she says the worst part of it was finding a drug that worked and then losing access because of insurance. This happened shortly after she gave birth to a daughter in 2022 and then endured intense joint pain.
“If I could take a blood test that tells me not to waste months or years of my life — absolutely,” she said. “If I could have started my current drug last fall and saved many months of not being able to engage with my baby on the floor — absolutely.”
This article originally appeared on KFFHealthNews.org. KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF — the independent source for health policy research, polling, and journalism.
Erinn Maury, MD, knew Remicade wasn’t the right drug for Patti Schulte, a patient with rheumatoid arthritis the physician saw at her Millersville, Maryland, practice. Schulte’s swollen, painful joints hadn’t responded to Enbrel or Humira, two drugs in the same class.
But the insurer insisted, so Schulte went on Remicade. It didn’t work either.
What’s more, Schulte suffered a severe allergic reaction to the infusion therapy, requiring a heavy dose of prednisone, a steroid with grave side effects if used at high doses for too long.
After 18 months, her insurer finally approved Maury’s drug of choice, Orencia. By then, Schulte’s vertebrae, weakened by prednisone, had started cracking. She was only 60.
It’s also a story of how doctors are steered by pharmacy benefit managers — the middlemen of the drug market — as well as by insurers.
Once people with inflammatory conditions such as rheumatoid arthritis reach a certain stage, the first prescription offered is typically Humira, the best-selling drug in history, and part of a class known as tumor necrosis factor inhibitors, or TNFis, which fail to significantly help about half of the patients who take it.
“We practice rheumatology without any help,” said Vibeke Strand, a rheumatologist and adjunct clinical professor at Stanford. She bemoaned the lack of tools available to choose the right drug while bristling at corporate intervention in the decision. “We are told by the insurer what to prescribe to the patient. After they fail methotrexate, it’s a TNF inhibitor, almost always Humira. And that’s not OK.”
If there’s a shred of hope in this story, it’s that a blood test, PrismRA, may herald an era of improved care for patients with rheumatoid arthritis and other autoimmune conditions. But first, it must be embraced by insurers.
PrismRA employs a predictive model that combines clinical factors, blood tests, and 19 gene patterns to identify the roughly 60% of patients who are very unlikely to respond to a TNFi drug.
Over the past 25 years, drug companies have introduced five new classes of autoimmune drugs. TNFis were the first to market, starting in the late 1990s.
Some 1.3 million Americans have rheumatoid arthritis, a disease in which a person’s immune system attacks their joints, causing crippling pain and, if improperly treated, disfigurement. The newer drugs, mostly so-called biologics, are also used by some of the 25 million or more Americans with other autoimmune diseases, such as lupus, Crohn’s disease, and psoriasis. Typically costing tens of thousands of dollars annually, the drugs are prescribed after a patient fails to respond to older, cheaper drugs like methotrexate.
Until recently, rheumatologists have had few ways to predict which of the new drugs would work best on which patients. Often, “it’s a coin flip whether I prescribe drug A or B,” said Jeffrey Curtis, MD, a rheumatology professor at the University of Alabama-Birmingham.
Yet about 90% of the patients who are given one of these advanced drugs start on a TNFi, although there’s often no reason to think a TNFi will work better than another type.
Under these puzzling circumstances, it’s often the insurer rather than the doctor who chooses the patient’s drug. Insurers lean toward TNFis such as adalimumab, commonly sold as brand name Humira, in part because they get large rebates from manufacturers for using them. Although the size of such payments is a trade secret, AbbVie is said to be offering rebates to insurers of up to 60% of Humira’s price. That has enabled it to control 98.5% of the US adalimumab market, even though it has eight biosimilar competitors.
PrismRA’s developer, Scipher Medicine, has provided more than 26,000 test results, rarely covered by insurance. But on October 15, the Centers for Medicare & Medicaid began reimbursing for the test, and its use is expected to rise. At least two other companies are developing drug-matching tests for patients with rheumatoid arthritis.
Although critics say PrismRA is not always useful, it is likely to be the first in a series of diagnostics anticipated over the next decade that could reduce the time that patients with autoimmune disease suffer on the wrong drug.
Academics, small biotechs, and large pharmaceutical companies are investing in methods to distinguish the biological pathways involved in these diseases and the best way to treat each one. This approach, called precision medicine, has existed for years in cancer medicine, in which it’s routine to test the genetics of patients’ tumors to determine the appropriate drug treatment.
“You wouldn’t give Herceptin to a breast cancer patient without knowing whether her tumor was HER2-positive,” said Costantino Pitzalis, MD, a rheumatology professor at the William Harvey Research Institute in London, England. He was speaking before a well-attended session at an American College of Rheumatology conference in San Diego in November. “Why do we not use biopsies or seek molecular markers in rheumatoid arthritis?”
It’s not only patients and doctors who have a stake in which drugs work best for a given person.
When Remicade failed and Schulte waited for the insurer to approve Orencia, she insisted on keeping her job as an accountant. But as her prednisone-related spinal problems worsened, Schulte was forced to retire, go on Medicaid, and seek disability, something she had always sworn to avoid.
Now taxpayers, rather than the insurer, are covering Schulte’s medical bills, Dr. Maury noted.
Precision medicine hasn’t seemed like a priority for large makers of autoimmune drugs, which presumably have some knowledge of which patients are most likely to benefit from their drugs, because they have tested and sold millions of doses over the years. By offering rebate incentives to insurers, companies like AbbVie, which makes Humira, can guarantee theirs are the drugs of choice with insurers.
“If you were AbbVie,” Dr. Curtis said, “why would you ever want to publish data showing who’s not going to do well on your drug, if, in the absence of the test, everyone will start with your drug first?”
What Testing Could Do
Medicare and commercial insurers haven’t yet set a price for PrismRA, but it could save insurers thousands of dollars a year for each patient it helps, according to Krishna Patel, PharmD, Scipher’s associate director of medical affairs.
“If the test cost $750, I still only need it once, and it costs less than a month of whatever drug is not going to work very well for you,” said Dr. Curtis, a coauthor of some studies of the test. “The economics of a biomarker that’s anything but worthless is pretty favorable because our biologics and targeted drugs are so expensive.”
Patients are enthusiastic about the test because so many have had to take TNFis that didn’t work. Many insurers require patients to try a second TNFi and sometimes a third.
Jen Weaver, a patient advocate and mother of three, got little benefit from hydroxychloroquine, sulfasalazine, methotrexate, and Orencia, a non-TNFi biologic therapy, before finding some relief in another, Actemra. But she was taken off that drug when her white blood cells plunged, and the next three drugs she tried — all TNFis — caused allergic reactions, culminating with an outbreak of pus-filled sores. Another drug, Otezla, eventually seemed to help heal the sores, and she’s been stable on it since in combination with methotrexate, Ms. Weaver said.
“What is needed is to substantially shorten this trial-and-error period for patients,” said Shilpa Venkatachalam, PhD, herself a patient and the director of research operations at the Global Healthy Living Foundation. “There’s a lot of anxiety and frustration, weeks in pain wondering whether a drug is going to work for you and what to do if it doesn’t.” A survey by her group found that 91% of patients worried their medications would stop working. And there is evidence that the longer it takes to resolve arthritis symptoms, the less chance they will ever stop.
How insurers will respond to the availability of tests isn’t clear, partly because the arrival of new biosimilar drugs — essentially generic versions — is making TNFis cheaper for insurance plans. While Humira still dominates, AbbVie has increased rebates to insurers, in effect lowering its cost. Lower prices make the PrismRA test less appealing to insurers because widespread use of the test could cut TNFi prescriptions by up to a third.
However, rheumatologist John B. Boone, MD, in Louisville, Kentucky, found to his surprise that insurers mostly accepted alternative prescriptions for 41 patients whom the test showed unlikely to respond to TNFis as part of a clinical trial. Dr. Boone receives consulting fees from Scipher.
Although the test didn’t guarantee good outcomes, he said, the few patients given TNFis despite the test results almost all did poorly on that regimen.
Scientists from AbbVie, which makes several rheumatology drugs in addition to Humira, presented a study at the San Diego conference examining biomarkers that might show which patients would respond to Rinvoq, a new immune-suppressing drug in a class known as the JAK inhibitors. When asked about its use of precision medicine, AbbVie declined to comment.
Over two decades, Humira has been a blockbuster drug for AbbVie. The company sold more than $3.5 billion worth of Humira in the third quarter of 2023, 36% less than a year ago. Sales of Rinvoq, which AbbVie is marketing as a treatment for patients failed by Humira and its class, jumped 60% to $1.1 billion.
What Patients Want
Shannan O’Hara-Levi, a 38-year-old in Monroe, New York, has been on scores of drugs and supplements since being diagnosed with juvenile arthritis at age 3. She’s been nauseated, fatigued, and short of breath and has suffered allergic reactions, but she says the worst part of it was finding a drug that worked and then losing access because of insurance. This happened shortly after she gave birth to a daughter in 2022 and then endured intense joint pain.
“If I could take a blood test that tells me not to waste months or years of my life — absolutely,” she said. “If I could have started my current drug last fall and saved many months of not being able to engage with my baby on the floor — absolutely.”
This article originally appeared on KFFHealthNews.org. KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF — the independent source for health policy research, polling, and journalism.
Erinn Maury, MD, knew Remicade wasn’t the right drug for Patti Schulte, a patient with rheumatoid arthritis the physician saw at her Millersville, Maryland, practice. Schulte’s swollen, painful joints hadn’t responded to Enbrel or Humira, two drugs in the same class.
But the insurer insisted, so Schulte went on Remicade. It didn’t work either.
What’s more, Schulte suffered a severe allergic reaction to the infusion therapy, requiring a heavy dose of prednisone, a steroid with grave side effects if used at high doses for too long.
After 18 months, her insurer finally approved Maury’s drug of choice, Orencia. By then, Schulte’s vertebrae, weakened by prednisone, had started cracking. She was only 60.
It’s also a story of how doctors are steered by pharmacy benefit managers — the middlemen of the drug market — as well as by insurers.
Once people with inflammatory conditions such as rheumatoid arthritis reach a certain stage, the first prescription offered is typically Humira, the best-selling drug in history, and part of a class known as tumor necrosis factor inhibitors, or TNFis, which fail to significantly help about half of the patients who take it.
“We practice rheumatology without any help,” said Vibeke Strand, a rheumatologist and adjunct clinical professor at Stanford. She bemoaned the lack of tools available to choose the right drug while bristling at corporate intervention in the decision. “We are told by the insurer what to prescribe to the patient. After they fail methotrexate, it’s a TNF inhibitor, almost always Humira. And that’s not OK.”
If there’s a shred of hope in this story, it’s that a blood test, PrismRA, may herald an era of improved care for patients with rheumatoid arthritis and other autoimmune conditions. But first, it must be embraced by insurers.
PrismRA employs a predictive model that combines clinical factors, blood tests, and 19 gene patterns to identify the roughly 60% of patients who are very unlikely to respond to a TNFi drug.
Over the past 25 years, drug companies have introduced five new classes of autoimmune drugs. TNFis were the first to market, starting in the late 1990s.
Some 1.3 million Americans have rheumatoid arthritis, a disease in which a person’s immune system attacks their joints, causing crippling pain and, if improperly treated, disfigurement. The newer drugs, mostly so-called biologics, are also used by some of the 25 million or more Americans with other autoimmune diseases, such as lupus, Crohn’s disease, and psoriasis. Typically costing tens of thousands of dollars annually, the drugs are prescribed after a patient fails to respond to older, cheaper drugs like methotrexate.
Until recently, rheumatologists have had few ways to predict which of the new drugs would work best on which patients. Often, “it’s a coin flip whether I prescribe drug A or B,” said Jeffrey Curtis, MD, a rheumatology professor at the University of Alabama-Birmingham.
Yet about 90% of the patients who are given one of these advanced drugs start on a TNFi, although there’s often no reason to think a TNFi will work better than another type.
Under these puzzling circumstances, it’s often the insurer rather than the doctor who chooses the patient’s drug. Insurers lean toward TNFis such as adalimumab, commonly sold as brand name Humira, in part because they get large rebates from manufacturers for using them. Although the size of such payments is a trade secret, AbbVie is said to be offering rebates to insurers of up to 60% of Humira’s price. That has enabled it to control 98.5% of the US adalimumab market, even though it has eight biosimilar competitors.
PrismRA’s developer, Scipher Medicine, has provided more than 26,000 test results, rarely covered by insurance. But on October 15, the Centers for Medicare & Medicaid began reimbursing for the test, and its use is expected to rise. At least two other companies are developing drug-matching tests for patients with rheumatoid arthritis.
Although critics say PrismRA is not always useful, it is likely to be the first in a series of diagnostics anticipated over the next decade that could reduce the time that patients with autoimmune disease suffer on the wrong drug.
Academics, small biotechs, and large pharmaceutical companies are investing in methods to distinguish the biological pathways involved in these diseases and the best way to treat each one. This approach, called precision medicine, has existed for years in cancer medicine, in which it’s routine to test the genetics of patients’ tumors to determine the appropriate drug treatment.
“You wouldn’t give Herceptin to a breast cancer patient without knowing whether her tumor was HER2-positive,” said Costantino Pitzalis, MD, a rheumatology professor at the William Harvey Research Institute in London, England. He was speaking before a well-attended session at an American College of Rheumatology conference in San Diego in November. “Why do we not use biopsies or seek molecular markers in rheumatoid arthritis?”
It’s not only patients and doctors who have a stake in which drugs work best for a given person.
When Remicade failed and Schulte waited for the insurer to approve Orencia, she insisted on keeping her job as an accountant. But as her prednisone-related spinal problems worsened, Schulte was forced to retire, go on Medicaid, and seek disability, something she had always sworn to avoid.
Now taxpayers, rather than the insurer, are covering Schulte’s medical bills, Dr. Maury noted.
Precision medicine hasn’t seemed like a priority for large makers of autoimmune drugs, which presumably have some knowledge of which patients are most likely to benefit from their drugs, because they have tested and sold millions of doses over the years. By offering rebate incentives to insurers, companies like AbbVie, which makes Humira, can guarantee theirs are the drugs of choice with insurers.
“If you were AbbVie,” Dr. Curtis said, “why would you ever want to publish data showing who’s not going to do well on your drug, if, in the absence of the test, everyone will start with your drug first?”
What Testing Could Do
Medicare and commercial insurers haven’t yet set a price for PrismRA, but it could save insurers thousands of dollars a year for each patient it helps, according to Krishna Patel, PharmD, Scipher’s associate director of medical affairs.
“If the test cost $750, I still only need it once, and it costs less than a month of whatever drug is not going to work very well for you,” said Dr. Curtis, a coauthor of some studies of the test. “The economics of a biomarker that’s anything but worthless is pretty favorable because our biologics and targeted drugs are so expensive.”
Patients are enthusiastic about the test because so many have had to take TNFis that didn’t work. Many insurers require patients to try a second TNFi and sometimes a third.
Jen Weaver, a patient advocate and mother of three, got little benefit from hydroxychloroquine, sulfasalazine, methotrexate, and Orencia, a non-TNFi biologic therapy, before finding some relief in another, Actemra. But she was taken off that drug when her white blood cells plunged, and the next three drugs she tried — all TNFis — caused allergic reactions, culminating with an outbreak of pus-filled sores. Another drug, Otezla, eventually seemed to help heal the sores, and she’s been stable on it since in combination with methotrexate, Ms. Weaver said.
“What is needed is to substantially shorten this trial-and-error period for patients,” said Shilpa Venkatachalam, PhD, herself a patient and the director of research operations at the Global Healthy Living Foundation. “There’s a lot of anxiety and frustration, weeks in pain wondering whether a drug is going to work for you and what to do if it doesn’t.” A survey by her group found that 91% of patients worried their medications would stop working. And there is evidence that the longer it takes to resolve arthritis symptoms, the less chance they will ever stop.
How insurers will respond to the availability of tests isn’t clear, partly because the arrival of new biosimilar drugs — essentially generic versions — is making TNFis cheaper for insurance plans. While Humira still dominates, AbbVie has increased rebates to insurers, in effect lowering its cost. Lower prices make the PrismRA test less appealing to insurers because widespread use of the test could cut TNFi prescriptions by up to a third.
However, rheumatologist John B. Boone, MD, in Louisville, Kentucky, found to his surprise that insurers mostly accepted alternative prescriptions for 41 patients whom the test showed unlikely to respond to TNFis as part of a clinical trial. Dr. Boone receives consulting fees from Scipher.
Although the test didn’t guarantee good outcomes, he said, the few patients given TNFis despite the test results almost all did poorly on that regimen.
Scientists from AbbVie, which makes several rheumatology drugs in addition to Humira, presented a study at the San Diego conference examining biomarkers that might show which patients would respond to Rinvoq, a new immune-suppressing drug in a class known as the JAK inhibitors. When asked about its use of precision medicine, AbbVie declined to comment.
Over two decades, Humira has been a blockbuster drug for AbbVie. The company sold more than $3.5 billion worth of Humira in the third quarter of 2023, 36% less than a year ago. Sales of Rinvoq, which AbbVie is marketing as a treatment for patients failed by Humira and its class, jumped 60% to $1.1 billion.
What Patients Want
Shannan O’Hara-Levi, a 38-year-old in Monroe, New York, has been on scores of drugs and supplements since being diagnosed with juvenile arthritis at age 3. She’s been nauseated, fatigued, and short of breath and has suffered allergic reactions, but she says the worst part of it was finding a drug that worked and then losing access because of insurance. This happened shortly after she gave birth to a daughter in 2022 and then endured intense joint pain.
“If I could take a blood test that tells me not to waste months or years of my life — absolutely,” she said. “If I could have started my current drug last fall and saved many months of not being able to engage with my baby on the floor — absolutely.”
This article originally appeared on KFFHealthNews.org. KFF Health News is a national newsroom that produces in-depth journalism about health issues and is one of the core operating programs at KFF — the independent source for health policy research, polling, and journalism.
Monitoring Tech for Pulmonary Disorders Moving Beyond Wearables
, but, as with any emergent technology, pitfalls come along with the promise and potential.
Meanwhile, technology to remotely monitor respiratory diseases is advancing into other modalities. In recent months, researchers have reported on an artificial intelligence–aided home stethoscope to monitor asthma exacerbations and an ingestible electronic capsule, which has shown some facility for continuous, remote monitoring of sleep apnea and opioid induced respiratory depression.
“Smartphones and wearable technology in health care are here to stay,” Mariam Louis, MD, pulmonologist and sleep medicine physician at the University of Florida Health and chair of the nonrespiratory sleep section of the Sleep Medicine Network with the American College of Chest Physicians, said in an interview.
“It is an exciting field, as it encourages patients to be actively involved in their medical care and can potentially offer more real-time feedback regarding the patient’s medical conditions,” she said. “There are currently many apps that are being used to monitor sleep and other diseases. However, the technology is still rudimentary, and much more research is needed to see if these apps are accurate and dependable.”
Studies in the past few months have reported on the accuracy of 18 wearable sleep-tracker devices, finding they overestimated sleep duration by 19 minutes on average (Sleep. 2023 Nov 8. doi: 10.1093/sleep/zsad288). Researchers in the United States also recently reported on the first human trial of an ingestible pill for monitoring sleep apnea that sends data to a receiving device up to six feet away (Device. 2023 Nov 17. doi: 10.1016/j.device.2023.100125), and a group in Poland reported than an AI-aided home stethoscope provided reliable information on asthma exacerbations in 149 patients (Ann Fam Med. 2023;21:517-25).
Targeting Challenges With Polysomnography
All of these technologies aim to overcome challenges with traditional devices, such as polysomnography (PSG) for evaluating sleep. Jaques Reifman, PhD, a senior research scientist at the U.S. Army Medical Research and Development Command in Fort Detrick, Maryland, led the study of 18 wearable sleep trackers. “Both polysomnography and sleep tracking devices in a sense are attempting to reach the same goal: they’re trying to estimate certain sleep parameters,” Dr. Reifman said in an interview.
“But they use very different signals,” he added, noting that PSG uses electroencephalography (EEG) to measure electrical signals in the skull whereas most sleep trackers used an accelerometer to measure body movement. “As your wrist moves around, it determines if you are moving or not,” Dr. Reifman said.
“Each of them have their plusses and minuses,” he added. PSG, while it’s considered the gold standard for measuring sleep, isn’t a consumer product. “It generally requires a very sophisticated data acquisition system; they are laden with motion artifacts and you have to have software to remove them before you analyze the data,” Dr. Reifman said. “They generally require an expert to interpret the results, although lately there are a few AI-based algorithms that you can provide the EEG signals to and it does score those stages for you”
Sleep trackers, on the other hand, are consumer products. “They can be used outside the lab, and you can use them to record for long periods of time, which is not really possible with PSG,” Dr. Reifman said. “They are low cost, they are easy to use, small size, and folks have developed algorithms that can directly tell the consumer you slept seven hours last night.
“In that sense, they’re comfortable to use as opposed to using an almost-like shower cap with the EEG and face sensors as part of the PSG montage.”
However, what sleep trackers offer in convenience, they lack in accuracy. “There are things they just cannot do based on the limitations of the signals that they use,” Dr. Reifman said.
The study was actually a meta-analysis of 14 different studies that evaluated 18 different sleep-tracking devices in 364 patients. The meta-analysis found wide variability in accuracy between devices; for example, a 75-minute overestimation of sleep with one device and a one-minute overestimation with another.
And different studies reported variations with the same tracker or different models of a tracker. The Fitbit Charge 2, for example, was found to underestimate sleep by 12 minutes in one study and overestimate sleep by 9 minutes in another, while the Fitbit HR Charge was found to overestimate sleep by 52 minutes in a third study.
The meta-analysis found while sleep trackers have high sensitivity (>90%), they had a relatively low specificity (<50%), Dr. Reifman noted.
“Because they are mainly based on the acceleration of your wrist, if you are laying down in bed and motionless after a few minutes the device is going to think you’re asleep when in reality you’re just motionless, daydreaming or trying to go to sleep but not sleeping, so the specificity to sleep is not that high,” he said.
These types of devices still have obstacles to overcome before they’re more widely used, Dr. Louis said. “All of these technologies are proprietary,” she said. “As such, little is known about the algorithms used to come up with the diagnosis or other conclusions. In addition, the majority of the data cannot be analyzed independently by the providers, limiting some of the usage of these devices for now.”
Early Study of Ingestible Capsule
To overcome some of those challenges with collecting data from wearables, researchers from the Massachusetts Institute of Technology and West Virginia University have worked with Celero Systems to develop a pill-sized capsule the patient swallows and which then collects vitals data from inside the gastrointestinal tract. The first in-human study evaluated the device, called the vitals-monitoring (VM) pill, in 10 patients. The study reported the data captured by the pill aligned with that gathered with standard sleep metrics and that it could detect sleep apnea episodes.
The study described the pill as a wireless device that uses a custom configuration of four off-the shelf integrated circuits — a microcontroller, accelerometer, memory component and radio signal — and electronic sensors for ballistic measurements from within the GI tract. The accelerometer measures movement of the abdomen during breathing.
Ingestible devices have actually been around for a couple of decades. The most common, the PillCam, is mostly used by gastroenterologists to capture images of the small intestine.
In the VM pill study, 3 of the 10 human volunteers had a diagnosis of either central or obstructive sleep apnea and wore a continuous positive airway pressure device during the study. The patients also had PSG. The study found that the heart rate accuracy of the VM pill was within 2.5 beats per minute of the PSG measure. The study found no significant difference in the ability of the VM pill to accurately measure respiratory rate with or without CPAP.
Since study completion, the device has been evaluated in another 10 patients, Ben Pless, CEO of Celero Systems, the company developing the VM pill and a coauthor of the study, said in an interview. All patients passed the capsule without any adverse events, he said.
The capsule carries the advantages of an implantable device without the surgery, Mr. Pless said. “In addition to the product being inside body, it is very good at measuring core temperature and, of course, there are diurnal variations in core temperature,” he said. “Even though this was not in the paper, we found the combination of monitoring respiration and core temperature is a very powerful way to do sleep staging in a completely unobtrusive and discrete way.”
The first study evaluated the overnight use of the VM pill, but future studies will evaluate longer duration of the device, first up to a week and then extending out to a month, with the goal of collecting data through the entire duration, Mr. Pless said.
“If you want to do ongoing monitoring for events that may have a low incidence, for example COPD exacerbations or some asthma which does not occur every day and you want to do long-term monitoring, an ingestible format where you ultimately take one capsule and you’re monitored for a month in a completely unobtrusive way would be a great way to do patient monitoring,” he said.
This platform could also collect multinight data for sleep studies, he added.
“While this is an exciting technology, there is much more to diagnosing sleep apnea than just heart rate and breathing,” Dr. Louis said. “During a sleep study, we look at oxygen levels, snoring, and many other variables.”
AI-Aided Stethoscope
The AI-aided stethoscope demonstrated an ability to collect reliable information on asthma exacerbations, the study in Poland found. “The parameters provided are effective for children, especially those younger than 5 years of age,” the study authors wrote.
The study enrolled patients of various ages with asthma, using the AI-aided stethoscope to monitor asthma-related physiologic parameters at home for six months. The stethoscope recorded auscultatory sounds from standard chest point and sent them to a dedicated mobile phone application in which an AI module automatically analyzed the recordings and displayed the results. The researchers trained the AI module using more than 10,000 recordings of respiratory sounds.
The study showed that a host of parameters — wheezes, rhonchi, coarse and fine crackles, heart rate, respiratory rate and inspiration-to-expiration duration ration — measured with the AI-aided stethoscope can detect asthma exacerbations without the need for obtaining peak expiratory flow measurements. It also showed a potential to make asthma diagnosis more straightforward in younger children.
“As we learn more and refine these technologies, we will be able to offer more patient centered and precise medicine to our patients, tailored specifically to their needs,” Dr. Louis said. “AI will certainly play a part in the future.”
Dr. Louis and Dr. Reifman have no relevant relationships to disclose. Mr. Pless is CEO of Celero Systems, a privately held company in Lincoln, Mass.
, but, as with any emergent technology, pitfalls come along with the promise and potential.
Meanwhile, technology to remotely monitor respiratory diseases is advancing into other modalities. In recent months, researchers have reported on an artificial intelligence–aided home stethoscope to monitor asthma exacerbations and an ingestible electronic capsule, which has shown some facility for continuous, remote monitoring of sleep apnea and opioid induced respiratory depression.
“Smartphones and wearable technology in health care are here to stay,” Mariam Louis, MD, pulmonologist and sleep medicine physician at the University of Florida Health and chair of the nonrespiratory sleep section of the Sleep Medicine Network with the American College of Chest Physicians, said in an interview.
“It is an exciting field, as it encourages patients to be actively involved in their medical care and can potentially offer more real-time feedback regarding the patient’s medical conditions,” she said. “There are currently many apps that are being used to monitor sleep and other diseases. However, the technology is still rudimentary, and much more research is needed to see if these apps are accurate and dependable.”
Studies in the past few months have reported on the accuracy of 18 wearable sleep-tracker devices, finding they overestimated sleep duration by 19 minutes on average (Sleep. 2023 Nov 8. doi: 10.1093/sleep/zsad288). Researchers in the United States also recently reported on the first human trial of an ingestible pill for monitoring sleep apnea that sends data to a receiving device up to six feet away (Device. 2023 Nov 17. doi: 10.1016/j.device.2023.100125), and a group in Poland reported than an AI-aided home stethoscope provided reliable information on asthma exacerbations in 149 patients (Ann Fam Med. 2023;21:517-25).
Targeting Challenges With Polysomnography
All of these technologies aim to overcome challenges with traditional devices, such as polysomnography (PSG) for evaluating sleep. Jaques Reifman, PhD, a senior research scientist at the U.S. Army Medical Research and Development Command in Fort Detrick, Maryland, led the study of 18 wearable sleep trackers. “Both polysomnography and sleep tracking devices in a sense are attempting to reach the same goal: they’re trying to estimate certain sleep parameters,” Dr. Reifman said in an interview.
“But they use very different signals,” he added, noting that PSG uses electroencephalography (EEG) to measure electrical signals in the skull whereas most sleep trackers used an accelerometer to measure body movement. “As your wrist moves around, it determines if you are moving or not,” Dr. Reifman said.
“Each of them have their plusses and minuses,” he added. PSG, while it’s considered the gold standard for measuring sleep, isn’t a consumer product. “It generally requires a very sophisticated data acquisition system; they are laden with motion artifacts and you have to have software to remove them before you analyze the data,” Dr. Reifman said. “They generally require an expert to interpret the results, although lately there are a few AI-based algorithms that you can provide the EEG signals to and it does score those stages for you”
Sleep trackers, on the other hand, are consumer products. “They can be used outside the lab, and you can use them to record for long periods of time, which is not really possible with PSG,” Dr. Reifman said. “They are low cost, they are easy to use, small size, and folks have developed algorithms that can directly tell the consumer you slept seven hours last night.
“In that sense, they’re comfortable to use as opposed to using an almost-like shower cap with the EEG and face sensors as part of the PSG montage.”
However, what sleep trackers offer in convenience, they lack in accuracy. “There are things they just cannot do based on the limitations of the signals that they use,” Dr. Reifman said.
The study was actually a meta-analysis of 14 different studies that evaluated 18 different sleep-tracking devices in 364 patients. The meta-analysis found wide variability in accuracy between devices; for example, a 75-minute overestimation of sleep with one device and a one-minute overestimation with another.
And different studies reported variations with the same tracker or different models of a tracker. The Fitbit Charge 2, for example, was found to underestimate sleep by 12 minutes in one study and overestimate sleep by 9 minutes in another, while the Fitbit HR Charge was found to overestimate sleep by 52 minutes in a third study.
The meta-analysis found while sleep trackers have high sensitivity (>90%), they had a relatively low specificity (<50%), Dr. Reifman noted.
“Because they are mainly based on the acceleration of your wrist, if you are laying down in bed and motionless after a few minutes the device is going to think you’re asleep when in reality you’re just motionless, daydreaming or trying to go to sleep but not sleeping, so the specificity to sleep is not that high,” he said.
These types of devices still have obstacles to overcome before they’re more widely used, Dr. Louis said. “All of these technologies are proprietary,” she said. “As such, little is known about the algorithms used to come up with the diagnosis or other conclusions. In addition, the majority of the data cannot be analyzed independently by the providers, limiting some of the usage of these devices for now.”
Early Study of Ingestible Capsule
To overcome some of those challenges with collecting data from wearables, researchers from the Massachusetts Institute of Technology and West Virginia University have worked with Celero Systems to develop a pill-sized capsule the patient swallows and which then collects vitals data from inside the gastrointestinal tract. The first in-human study evaluated the device, called the vitals-monitoring (VM) pill, in 10 patients. The study reported the data captured by the pill aligned with that gathered with standard sleep metrics and that it could detect sleep apnea episodes.
The study described the pill as a wireless device that uses a custom configuration of four off-the shelf integrated circuits — a microcontroller, accelerometer, memory component and radio signal — and electronic sensors for ballistic measurements from within the GI tract. The accelerometer measures movement of the abdomen during breathing.
Ingestible devices have actually been around for a couple of decades. The most common, the PillCam, is mostly used by gastroenterologists to capture images of the small intestine.
In the VM pill study, 3 of the 10 human volunteers had a diagnosis of either central or obstructive sleep apnea and wore a continuous positive airway pressure device during the study. The patients also had PSG. The study found that the heart rate accuracy of the VM pill was within 2.5 beats per minute of the PSG measure. The study found no significant difference in the ability of the VM pill to accurately measure respiratory rate with or without CPAP.
Since study completion, the device has been evaluated in another 10 patients, Ben Pless, CEO of Celero Systems, the company developing the VM pill and a coauthor of the study, said in an interview. All patients passed the capsule without any adverse events, he said.
The capsule carries the advantages of an implantable device without the surgery, Mr. Pless said. “In addition to the product being inside body, it is very good at measuring core temperature and, of course, there are diurnal variations in core temperature,” he said. “Even though this was not in the paper, we found the combination of monitoring respiration and core temperature is a very powerful way to do sleep staging in a completely unobtrusive and discrete way.”
The first study evaluated the overnight use of the VM pill, but future studies will evaluate longer duration of the device, first up to a week and then extending out to a month, with the goal of collecting data through the entire duration, Mr. Pless said.
“If you want to do ongoing monitoring for events that may have a low incidence, for example COPD exacerbations or some asthma which does not occur every day and you want to do long-term monitoring, an ingestible format where you ultimately take one capsule and you’re monitored for a month in a completely unobtrusive way would be a great way to do patient monitoring,” he said.
This platform could also collect multinight data for sleep studies, he added.
“While this is an exciting technology, there is much more to diagnosing sleep apnea than just heart rate and breathing,” Dr. Louis said. “During a sleep study, we look at oxygen levels, snoring, and many other variables.”
AI-Aided Stethoscope
The AI-aided stethoscope demonstrated an ability to collect reliable information on asthma exacerbations, the study in Poland found. “The parameters provided are effective for children, especially those younger than 5 years of age,” the study authors wrote.
The study enrolled patients of various ages with asthma, using the AI-aided stethoscope to monitor asthma-related physiologic parameters at home for six months. The stethoscope recorded auscultatory sounds from standard chest point and sent them to a dedicated mobile phone application in which an AI module automatically analyzed the recordings and displayed the results. The researchers trained the AI module using more than 10,000 recordings of respiratory sounds.
The study showed that a host of parameters — wheezes, rhonchi, coarse and fine crackles, heart rate, respiratory rate and inspiration-to-expiration duration ration — measured with the AI-aided stethoscope can detect asthma exacerbations without the need for obtaining peak expiratory flow measurements. It also showed a potential to make asthma diagnosis more straightforward in younger children.
“As we learn more and refine these technologies, we will be able to offer more patient centered and precise medicine to our patients, tailored specifically to their needs,” Dr. Louis said. “AI will certainly play a part in the future.”
Dr. Louis and Dr. Reifman have no relevant relationships to disclose. Mr. Pless is CEO of Celero Systems, a privately held company in Lincoln, Mass.
, but, as with any emergent technology, pitfalls come along with the promise and potential.
Meanwhile, technology to remotely monitor respiratory diseases is advancing into other modalities. In recent months, researchers have reported on an artificial intelligence–aided home stethoscope to monitor asthma exacerbations and an ingestible electronic capsule, which has shown some facility for continuous, remote monitoring of sleep apnea and opioid induced respiratory depression.
“Smartphones and wearable technology in health care are here to stay,” Mariam Louis, MD, pulmonologist and sleep medicine physician at the University of Florida Health and chair of the nonrespiratory sleep section of the Sleep Medicine Network with the American College of Chest Physicians, said in an interview.
“It is an exciting field, as it encourages patients to be actively involved in their medical care and can potentially offer more real-time feedback regarding the patient’s medical conditions,” she said. “There are currently many apps that are being used to monitor sleep and other diseases. However, the technology is still rudimentary, and much more research is needed to see if these apps are accurate and dependable.”
Studies in the past few months have reported on the accuracy of 18 wearable sleep-tracker devices, finding they overestimated sleep duration by 19 minutes on average (Sleep. 2023 Nov 8. doi: 10.1093/sleep/zsad288). Researchers in the United States also recently reported on the first human trial of an ingestible pill for monitoring sleep apnea that sends data to a receiving device up to six feet away (Device. 2023 Nov 17. doi: 10.1016/j.device.2023.100125), and a group in Poland reported than an AI-aided home stethoscope provided reliable information on asthma exacerbations in 149 patients (Ann Fam Med. 2023;21:517-25).
Targeting Challenges With Polysomnography
All of these technologies aim to overcome challenges with traditional devices, such as polysomnography (PSG) for evaluating sleep. Jaques Reifman, PhD, a senior research scientist at the U.S. Army Medical Research and Development Command in Fort Detrick, Maryland, led the study of 18 wearable sleep trackers. “Both polysomnography and sleep tracking devices in a sense are attempting to reach the same goal: they’re trying to estimate certain sleep parameters,” Dr. Reifman said in an interview.
“But they use very different signals,” he added, noting that PSG uses electroencephalography (EEG) to measure electrical signals in the skull whereas most sleep trackers used an accelerometer to measure body movement. “As your wrist moves around, it determines if you are moving or not,” Dr. Reifman said.
“Each of them have their plusses and minuses,” he added. PSG, while it’s considered the gold standard for measuring sleep, isn’t a consumer product. “It generally requires a very sophisticated data acquisition system; they are laden with motion artifacts and you have to have software to remove them before you analyze the data,” Dr. Reifman said. “They generally require an expert to interpret the results, although lately there are a few AI-based algorithms that you can provide the EEG signals to and it does score those stages for you”
Sleep trackers, on the other hand, are consumer products. “They can be used outside the lab, and you can use them to record for long periods of time, which is not really possible with PSG,” Dr. Reifman said. “They are low cost, they are easy to use, small size, and folks have developed algorithms that can directly tell the consumer you slept seven hours last night.
“In that sense, they’re comfortable to use as opposed to using an almost-like shower cap with the EEG and face sensors as part of the PSG montage.”
However, what sleep trackers offer in convenience, they lack in accuracy. “There are things they just cannot do based on the limitations of the signals that they use,” Dr. Reifman said.
The study was actually a meta-analysis of 14 different studies that evaluated 18 different sleep-tracking devices in 364 patients. The meta-analysis found wide variability in accuracy between devices; for example, a 75-minute overestimation of sleep with one device and a one-minute overestimation with another.
And different studies reported variations with the same tracker or different models of a tracker. The Fitbit Charge 2, for example, was found to underestimate sleep by 12 minutes in one study and overestimate sleep by 9 minutes in another, while the Fitbit HR Charge was found to overestimate sleep by 52 minutes in a third study.
The meta-analysis found while sleep trackers have high sensitivity (>90%), they had a relatively low specificity (<50%), Dr. Reifman noted.
“Because they are mainly based on the acceleration of your wrist, if you are laying down in bed and motionless after a few minutes the device is going to think you’re asleep when in reality you’re just motionless, daydreaming or trying to go to sleep but not sleeping, so the specificity to sleep is not that high,” he said.
These types of devices still have obstacles to overcome before they’re more widely used, Dr. Louis said. “All of these technologies are proprietary,” she said. “As such, little is known about the algorithms used to come up with the diagnosis or other conclusions. In addition, the majority of the data cannot be analyzed independently by the providers, limiting some of the usage of these devices for now.”
Early Study of Ingestible Capsule
To overcome some of those challenges with collecting data from wearables, researchers from the Massachusetts Institute of Technology and West Virginia University have worked with Celero Systems to develop a pill-sized capsule the patient swallows and which then collects vitals data from inside the gastrointestinal tract. The first in-human study evaluated the device, called the vitals-monitoring (VM) pill, in 10 patients. The study reported the data captured by the pill aligned with that gathered with standard sleep metrics and that it could detect sleep apnea episodes.
The study described the pill as a wireless device that uses a custom configuration of four off-the shelf integrated circuits — a microcontroller, accelerometer, memory component and radio signal — and electronic sensors for ballistic measurements from within the GI tract. The accelerometer measures movement of the abdomen during breathing.
Ingestible devices have actually been around for a couple of decades. The most common, the PillCam, is mostly used by gastroenterologists to capture images of the small intestine.
In the VM pill study, 3 of the 10 human volunteers had a diagnosis of either central or obstructive sleep apnea and wore a continuous positive airway pressure device during the study. The patients also had PSG. The study found that the heart rate accuracy of the VM pill was within 2.5 beats per minute of the PSG measure. The study found no significant difference in the ability of the VM pill to accurately measure respiratory rate with or without CPAP.
Since study completion, the device has been evaluated in another 10 patients, Ben Pless, CEO of Celero Systems, the company developing the VM pill and a coauthor of the study, said in an interview. All patients passed the capsule without any adverse events, he said.
The capsule carries the advantages of an implantable device without the surgery, Mr. Pless said. “In addition to the product being inside body, it is very good at measuring core temperature and, of course, there are diurnal variations in core temperature,” he said. “Even though this was not in the paper, we found the combination of monitoring respiration and core temperature is a very powerful way to do sleep staging in a completely unobtrusive and discrete way.”
The first study evaluated the overnight use of the VM pill, but future studies will evaluate longer duration of the device, first up to a week and then extending out to a month, with the goal of collecting data through the entire duration, Mr. Pless said.
“If you want to do ongoing monitoring for events that may have a low incidence, for example COPD exacerbations or some asthma which does not occur every day and you want to do long-term monitoring, an ingestible format where you ultimately take one capsule and you’re monitored for a month in a completely unobtrusive way would be a great way to do patient monitoring,” he said.
This platform could also collect multinight data for sleep studies, he added.
“While this is an exciting technology, there is much more to diagnosing sleep apnea than just heart rate and breathing,” Dr. Louis said. “During a sleep study, we look at oxygen levels, snoring, and many other variables.”
AI-Aided Stethoscope
The AI-aided stethoscope demonstrated an ability to collect reliable information on asthma exacerbations, the study in Poland found. “The parameters provided are effective for children, especially those younger than 5 years of age,” the study authors wrote.
The study enrolled patients of various ages with asthma, using the AI-aided stethoscope to monitor asthma-related physiologic parameters at home for six months. The stethoscope recorded auscultatory sounds from standard chest point and sent them to a dedicated mobile phone application in which an AI module automatically analyzed the recordings and displayed the results. The researchers trained the AI module using more than 10,000 recordings of respiratory sounds.
The study showed that a host of parameters — wheezes, rhonchi, coarse and fine crackles, heart rate, respiratory rate and inspiration-to-expiration duration ration — measured with the AI-aided stethoscope can detect asthma exacerbations without the need for obtaining peak expiratory flow measurements. It also showed a potential to make asthma diagnosis more straightforward in younger children.
“As we learn more and refine these technologies, we will be able to offer more patient centered and precise medicine to our patients, tailored specifically to their needs,” Dr. Louis said. “AI will certainly play a part in the future.”
Dr. Louis and Dr. Reifman have no relevant relationships to disclose. Mr. Pless is CEO of Celero Systems, a privately held company in Lincoln, Mass.
Depression Medications
Navigating Hair Loss in Medical School: Experiences of 2 Young Black Women
As medical students, we often assume we are exempt from the diagnoses we learn about. During the first 2 years of medical school, we learn about alopecia as a condition that may be associated with stress, hormonal imbalances, nutrient deficiencies, and aging. However, our curricula do not explore the subtypes, psychosocial impact, or even the overwhelming number of Black women who are disproportionately affected by alopecia. For Black women, hair is a colossal part of their cultural identity, learning from a young age how to nurture and style natural coils. It becomes devastating when women begin to lose them.
The diagnosis of alopecia subtypes in Black women has been explored in the literature; however, understanding the unique experiences of young Black women is an important part of patient care, as alopecia often is destructive to the patient’s self-image. Therefore, it is important to shed light on these experiences so others feel empowered and supported in their journeys. Herein, we share the experiences of 2 authors (J.D. and C.A.V.O.)—both young Black women—who navigated unexpected hair loss in medical school.
Jewell’s Story
During my first year of medical school, I noticed my hair was shedding more than usual, and my ponytail was not as thick as it once was. I also had an area in my crown that was abnormally thin. My parents suggested that it was a consequence of stress, but I knew something was not right. With only 1 Black dermatologist within 2 hours of Nashville, Tennessee, I remember worrying about seeing a dermatologist who did not understand Black hair. I still scheduled an appointment, but I remember debating if I should straighten my hair or wear my naturally curly Afro. The first dermatologist I saw diagnosed me with seborrheic dermatitis—without even examining my scalp. She told me that I had a “full head of hair” and that I had nothing to worry about. I was unconvinced. Weeks later, I met with another dermatologist who took the time to listen to my concerns. After a scalp biopsy and laboratory work, she diagnosed me with telogen effluvium and androgenetic alopecia. Months later, I had the opportunity to visit the Black dermatologist, and she diagnosed me with central centrifugal cicatricial alopecia. I am grateful for the earlier dermatologists I saw, but I finally feel at ease with my diagnosis and treatment plan after being seen by the latter.
Chidubem’s Story
From a young age, I was conditioned to think my hair was thick, unmanageable, and a nuisance. I grew accustomed to people yanking on my hair, and my gentle whispers of “this hurts” and “the braid is too tight” being ignored. That continued into adulthood. While studying for the US Medical Licensing Examination, I noticed a burning sensation on my scalp. I decided to ignore it. However, as the days progressed, the slight burning sensation turned into intense burning and itching. I still ignored it. Not only did I lack the funds for a dermatology appointment, but my licensing examination was approaching, and it was more important than anything related to my hair. After the examination, I eventually made an appointment with my primary care physician, who attributed my symptoms to the stressors of medical school. “I think you are having migraines,” she told me. So, I continued to ignore my symptoms. A year passed, and a hair braider pointed out that I had 2 well-defined bald patches on my scalp. I remember feeling angry and confused as to how I missed those findings. I could no longer ignore it—it bothered me less when no one else knew about it. I quickly made a dermatology appointment. Although I opted out of a biopsy, we decided to treat my hair loss empirically, and I have experienced drastic improvement.
Final Thoughts
We are 2 Black women living more than 500 miles away from each other at different medical institutions, yet we share the same experience, which many other women unfortunately face alone. It is not uncommon for us to feel unheard, dismissed, or misdiagnosed. We write this for the Black woman sorting through the feelings of confusion and shock as she traces the hairless spot on her scalp. We write this for the medical student ignoring their symptoms until after their examination. We even write this for any nondermatologists uncomfortable with diagnosing and treating textured hair. To improve patient satisfaction and overall health outcomes, physicians must approach patients with both knowledge and cultural competency. Most importantly, dermatologists (and other physicians) should be appropriately trained in not only the structural differences of textured hair but also the unique practices and beliefs among Black women in relation to their hair.
Acknowledgments—Jewell Dinkins is the inaugural recipient of the Janssen–Skin of Color Research Fellowship at Howard University (Washington, DC), and Chidubem A.V. Okeke is the inaugural recipient of the Women’s Dermatologic Society–La Roche-Posay dermatology fellowship at Howard University.
As medical students, we often assume we are exempt from the diagnoses we learn about. During the first 2 years of medical school, we learn about alopecia as a condition that may be associated with stress, hormonal imbalances, nutrient deficiencies, and aging. However, our curricula do not explore the subtypes, psychosocial impact, or even the overwhelming number of Black women who are disproportionately affected by alopecia. For Black women, hair is a colossal part of their cultural identity, learning from a young age how to nurture and style natural coils. It becomes devastating when women begin to lose them.
The diagnosis of alopecia subtypes in Black women has been explored in the literature; however, understanding the unique experiences of young Black women is an important part of patient care, as alopecia often is destructive to the patient’s self-image. Therefore, it is important to shed light on these experiences so others feel empowered and supported in their journeys. Herein, we share the experiences of 2 authors (J.D. and C.A.V.O.)—both young Black women—who navigated unexpected hair loss in medical school.
Jewell’s Story
During my first year of medical school, I noticed my hair was shedding more than usual, and my ponytail was not as thick as it once was. I also had an area in my crown that was abnormally thin. My parents suggested that it was a consequence of stress, but I knew something was not right. With only 1 Black dermatologist within 2 hours of Nashville, Tennessee, I remember worrying about seeing a dermatologist who did not understand Black hair. I still scheduled an appointment, but I remember debating if I should straighten my hair or wear my naturally curly Afro. The first dermatologist I saw diagnosed me with seborrheic dermatitis—without even examining my scalp. She told me that I had a “full head of hair” and that I had nothing to worry about. I was unconvinced. Weeks later, I met with another dermatologist who took the time to listen to my concerns. After a scalp biopsy and laboratory work, she diagnosed me with telogen effluvium and androgenetic alopecia. Months later, I had the opportunity to visit the Black dermatologist, and she diagnosed me with central centrifugal cicatricial alopecia. I am grateful for the earlier dermatologists I saw, but I finally feel at ease with my diagnosis and treatment plan after being seen by the latter.
Chidubem’s Story
From a young age, I was conditioned to think my hair was thick, unmanageable, and a nuisance. I grew accustomed to people yanking on my hair, and my gentle whispers of “this hurts” and “the braid is too tight” being ignored. That continued into adulthood. While studying for the US Medical Licensing Examination, I noticed a burning sensation on my scalp. I decided to ignore it. However, as the days progressed, the slight burning sensation turned into intense burning and itching. I still ignored it. Not only did I lack the funds for a dermatology appointment, but my licensing examination was approaching, and it was more important than anything related to my hair. After the examination, I eventually made an appointment with my primary care physician, who attributed my symptoms to the stressors of medical school. “I think you are having migraines,” she told me. So, I continued to ignore my symptoms. A year passed, and a hair braider pointed out that I had 2 well-defined bald patches on my scalp. I remember feeling angry and confused as to how I missed those findings. I could no longer ignore it—it bothered me less when no one else knew about it. I quickly made a dermatology appointment. Although I opted out of a biopsy, we decided to treat my hair loss empirically, and I have experienced drastic improvement.
Final Thoughts
We are 2 Black women living more than 500 miles away from each other at different medical institutions, yet we share the same experience, which many other women unfortunately face alone. It is not uncommon for us to feel unheard, dismissed, or misdiagnosed. We write this for the Black woman sorting through the feelings of confusion and shock as she traces the hairless spot on her scalp. We write this for the medical student ignoring their symptoms until after their examination. We even write this for any nondermatologists uncomfortable with diagnosing and treating textured hair. To improve patient satisfaction and overall health outcomes, physicians must approach patients with both knowledge and cultural competency. Most importantly, dermatologists (and other physicians) should be appropriately trained in not only the structural differences of textured hair but also the unique practices and beliefs among Black women in relation to their hair.
Acknowledgments—Jewell Dinkins is the inaugural recipient of the Janssen–Skin of Color Research Fellowship at Howard University (Washington, DC), and Chidubem A.V. Okeke is the inaugural recipient of the Women’s Dermatologic Society–La Roche-Posay dermatology fellowship at Howard University.
As medical students, we often assume we are exempt from the diagnoses we learn about. During the first 2 years of medical school, we learn about alopecia as a condition that may be associated with stress, hormonal imbalances, nutrient deficiencies, and aging. However, our curricula do not explore the subtypes, psychosocial impact, or even the overwhelming number of Black women who are disproportionately affected by alopecia. For Black women, hair is a colossal part of their cultural identity, learning from a young age how to nurture and style natural coils. It becomes devastating when women begin to lose them.
The diagnosis of alopecia subtypes in Black women has been explored in the literature; however, understanding the unique experiences of young Black women is an important part of patient care, as alopecia often is destructive to the patient’s self-image. Therefore, it is important to shed light on these experiences so others feel empowered and supported in their journeys. Herein, we share the experiences of 2 authors (J.D. and C.A.V.O.)—both young Black women—who navigated unexpected hair loss in medical school.
Jewell’s Story
During my first year of medical school, I noticed my hair was shedding more than usual, and my ponytail was not as thick as it once was. I also had an area in my crown that was abnormally thin. My parents suggested that it was a consequence of stress, but I knew something was not right. With only 1 Black dermatologist within 2 hours of Nashville, Tennessee, I remember worrying about seeing a dermatologist who did not understand Black hair. I still scheduled an appointment, but I remember debating if I should straighten my hair or wear my naturally curly Afro. The first dermatologist I saw diagnosed me with seborrheic dermatitis—without even examining my scalp. She told me that I had a “full head of hair” and that I had nothing to worry about. I was unconvinced. Weeks later, I met with another dermatologist who took the time to listen to my concerns. After a scalp biopsy and laboratory work, she diagnosed me with telogen effluvium and androgenetic alopecia. Months later, I had the opportunity to visit the Black dermatologist, and she diagnosed me with central centrifugal cicatricial alopecia. I am grateful for the earlier dermatologists I saw, but I finally feel at ease with my diagnosis and treatment plan after being seen by the latter.
Chidubem’s Story
From a young age, I was conditioned to think my hair was thick, unmanageable, and a nuisance. I grew accustomed to people yanking on my hair, and my gentle whispers of “this hurts” and “the braid is too tight” being ignored. That continued into adulthood. While studying for the US Medical Licensing Examination, I noticed a burning sensation on my scalp. I decided to ignore it. However, as the days progressed, the slight burning sensation turned into intense burning and itching. I still ignored it. Not only did I lack the funds for a dermatology appointment, but my licensing examination was approaching, and it was more important than anything related to my hair. After the examination, I eventually made an appointment with my primary care physician, who attributed my symptoms to the stressors of medical school. “I think you are having migraines,” she told me. So, I continued to ignore my symptoms. A year passed, and a hair braider pointed out that I had 2 well-defined bald patches on my scalp. I remember feeling angry and confused as to how I missed those findings. I could no longer ignore it—it bothered me less when no one else knew about it. I quickly made a dermatology appointment. Although I opted out of a biopsy, we decided to treat my hair loss empirically, and I have experienced drastic improvement.
Final Thoughts
We are 2 Black women living more than 500 miles away from each other at different medical institutions, yet we share the same experience, which many other women unfortunately face alone. It is not uncommon for us to feel unheard, dismissed, or misdiagnosed. We write this for the Black woman sorting through the feelings of confusion and shock as she traces the hairless spot on her scalp. We write this for the medical student ignoring their symptoms until after their examination. We even write this for any nondermatologists uncomfortable with diagnosing and treating textured hair. To improve patient satisfaction and overall health outcomes, physicians must approach patients with both knowledge and cultural competency. Most importantly, dermatologists (and other physicians) should be appropriately trained in not only the structural differences of textured hair but also the unique practices and beliefs among Black women in relation to their hair.
Acknowledgments—Jewell Dinkins is the inaugural recipient of the Janssen–Skin of Color Research Fellowship at Howard University (Washington, DC), and Chidubem A.V. Okeke is the inaugural recipient of the Women’s Dermatologic Society–La Roche-Posay dermatology fellowship at Howard University.
Practice Points
- Hair loss is a common dermatologic concern among Black women and can represent a diagnostic challenge to dermatologists who may not be familiar with textured hair.
- Dermatologists should practice cultural sensitivity and provide relevant recommendations to Black patients dealing with hair loss.
Thalidomide Analogue Drug Eruption Along the Lines of Blaschko
To the Editor:
Lenalidomide is a thalidomide analogue used to treat various hematologic malignancies, including non-Hodgkin lymphoma, myelodysplastic syndrome, and multiple myeloma (MM).1 Lenalidomide is referred to as a degrader therapeutic because it induces targeted protein degradation of disease-relevant proteins (eg, Ikaros family zinc finger protein 1 [IKZF1], Ikaros family zinc finger protein 3 [IKZF3], and casein kinase I isoform-α [CK1α]) as its primary mechanism of action.1,2 Although cutaneous adverse events are relatively common among thalidomide analogues, the morphologic and histopathologic descriptions of these drug eruptions have not been fully elucidated.3,4 We report a novel pityriasiform drug eruption followed by a clinical eruption suggestive of blaschkitis in a patient with MM who was being treated with lenalidomide.
A 76-year-old man presented to the dermatology clinic with a progressive, mildly pruritic eruption on the chest and axillae of 1 year’s duration. He had a medical history of chronic hepatitis B, malignant carcinoid tumor of the colon, prostate cancer, and MM. The eruption emerged 1 to 2 weeks after the patient started oral lenalidomide 10 mg/d and oral dexamethasone40 mg/wk following autologous stem cell transplantation for MM. The patient had not received any other therapy for MM.
Physical examination revealed multiple erythematous, hyperpigmented, scaly papules and plaques on the lateral chest and within the axillae (Figure 1). A skin biopsy from the left axilla demonstrated a mild lichenoid and perivascular lymphocytic infiltrate with scattered eosinophils, neutrophils, and extravasated erythrocytes. The overlying epidermis showed spongiosis with parakeratosis in addition to lymphocytic exocytosis (Figure 2). No fungal organisms were highlighted on periodic acid–Schiff staining. After this evaluation, we recommended that the patient discontinue lenalidomide and start taking a topical over-the-counter corticosteroid for 2 weeks. Over time, he noted marked improvement in the eruption and associated pruritus.
After a drug holiday of 2 months, the patient resumed a maintenance dosage of oral lenalidomide 10 mg/d. Four or 5 days after restarting lenalidomide, a pruritic eruption appeared that involved the axillae and the left lower abdomen, circling around to the left lower back. The axillary eruption resolved with a topical over-the-counter corticosteroid; the abdominal eruption persisted.
At the 3-month follow-up visit, physical examination revealed erythematous macules and papules that coalesced over a salmon-colored base along the lines of Blaschko extending from the left lower abdominal quadrant, crossing the left flank, and continuing to the left lower back without crossing the midline (Figure 3).
We recommended that the patient continue treatment through this eruption; he was instructed to apply a corticosteroid cream and resume lenalidomide at the maintenance dosage. A month later, he reported that the eruption and associated pruritus resolved with the corticosteroid cream and resumption of the maintenance dose of lenalidomide. The patient noted no further spread of the eruption.
Cutaneous adverse events are common following lenalidomide. In prior trials, the overall incidence of any-grade rash following lenalidomide exposure was 22% to 33%.5 A meta-analysis of 10 trials determined the overall incidence of all-grade and high-grade cutaneous adverse events after exposure to lenalidomide was 27.2% and 3.6%, respectively.6 Our case represents a pityriasiform eruption due to lenalidomide followed by a secondary eruption suggestive of blaschkitis.
The rash due to lenalidomide has been described as morbilliform, urticarial, dermatitic, acneform, and undefined.7 Lenalidomide-induced rash typically develops during the first month of therapy, similar to our patient’s presentation. It has even been observed in the first week of therapy.8 Severe reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.5,6 Risk factors associated with rash secondary to lenalidomide include advanced age (≥70 years), presence of Bence-Jones protein-type MM in urine, and no prior chemotherapy.8 Our patient had 2 of these risk factors: advanced age and no prior chemotherapy for MM. The exact pathogenesis by which lenalidomide leads to a pityriasiform eruption, as in our patient, or to a rash in general is unclear. Studies have hypothesized that a lenalidomide-induced rash could be attributable to a delayed hypersensitivity type IV reaction or to a reaction related to the molecular mechanism of action of the drug.9
At the molecular level, the antimyeloma effects of lenalidomide include promoting degradation of transcription factors IKZF1 and IKZF3, which subsequently increases production of IL-2.1,2,9 Recombinant IL-2 has been associated with an increased incidence of rash in other cancers.9 Overexpression of programmed death 1(PD-1) and its ligand (PD-L1) has been demonstrated in MM; lenalidomide has been shown to downregulate both PD-1 and PD-L1. Patients receiving PD-1 and PD-L1 inhibitors commonly have developed rash.9 However, the association between lenalidomide and its downregulation of PD-1 and PD-L1 leading to rash has not been fully elucidated. Given the multiple malignancies in our patient—MM, prostate cancer, malignant carcinoid tumor—an underlying paraneoplastic phenomenon may be possible. Additionally, because our patient initially received dexamethasone along with lenalidomide, the manifestation of the initial pityriasiform rash may have been less severe due to the steroid use. Although our patient underwent a 2-month drug holiday following the initial pityriasiform eruption, most lenalidomide-induced rashes do not necessitate discontinuation of the drug.5,7
Our patient’s secondary drug eruption was clinically suggestive of lenalidomide-induced blaschkitis. A report of a German patient with plasmacytoma described a unilateral papular exanthem that developed 4 months after lenalidomide was initiated.10 The papular exanthem following the lines of Blaschko lines extended from that patient’s posterior left foot to the calf and on to the thigh and flank,10 which was more extensive than our patient’s eruption. Blaschkitis in this patient resolved with a corticosteroid cream and UV light therapy10; lenalidomide was not discontinued, similar to our patient.
The pathogenesis of our patient’s secondary eruption that preferentially involved the lines of Blaschko is unclear. After the initial pityriasiform eruption, the secondary eruption was blaschkitis. Distinguishing dermatomes from the lines of Blaschko, which are thought to represent pathways of epidermal cell migration and proliferation during embryologic development, is important. Genodermatoses such as incontinentia pigmenti and hypomelanosis of Ito involve the lines of Blaschko11; other disorders in the differential diagnosis of linear configurations include linear lichen planus, linear cutaneous lupus erythematosus, linear morphea, and lichen striatus.11 Notably, drug-induced blaschkitis is rare.
Cutaneous adverse reactions from thalidomide analogues are relatively common. Our case of lenalidomide-associated blaschkitis that developed following an initial pityriasiform drug eruption in a patient with MM highlights that dermatologists need to collaborate with the oncologist regarding the severity of drug eruptions to determine if the patient should continue treatment through the cutaneous eruptions or discontinue a vital medication.
- Jan M, Sperling AS, Ebert BL. Cancer therapies based on targeted protein degradation—lessons learned with lenalidomide. Nat Rev Clin Oncol. 2021;18:401-417. doi:10.1038/s41571-021-00479-z
- Shah UA, Mailankody S. Emerging immunotherapies in multiple myeloma. BMJ. 2020;370:3176. doi:10.1136/BMJ.M3176
- Richardson PG, Blood E, Mitsiades CS, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006;108:3458-3464. doi:10.1182/BLOOD-2006-04-015909
- Benboubker L, Dimopoulos MA, Dispenzieri A, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014;371:906-917. doi:10.1056/NEJMOA1402551
- Tinsley SM, Kurtin SE, Ridgeway JA. Practical management of lenalidomide-related rash. Clin Lymphoma Myeloma Leuk. 2015;15(suppl):S64-S69. doi:10.1016/J.CLML.2015.02.008
- Nardone B, Wu S, Garden BC, et al. Risk of rash associated with lenalidomide in cancer patients: a systematic review of the literature and meta-analysis. Clin Lymphoma Myeloma Leuk. 2013;13:424-429. doi:10.1016/J.CLML.2013.03.006
- Sviggum HP, Davis MDP, Rajkumar SV, et al. Dermatologic adverse effects of lenalidomide therapy for amyloidosis and multiple myeloma. Arch Dermatol. 2006;142:1298-1302. doi:10.1001/ARCHDERM.142.10.1298
- Sugi T, Nishigami Y, Saigo H, et al. Analysis of risk factors for lenalidomide-associated skin rash in patients with multiple myeloma. Leuk Lymphoma. 2021;62:1405-1410. doi:10.1080/10428194.2021.1876867
- Barley K, He W, Agarwal S, et al. Outcomes and management of lenalidomide-associated rash in patients with multiple myeloma. Leuk Lymphoma. 2016;57:2510-2515. doi:10.3109/10428194.2016.1151507
- Grape J, Frosch P. Papular drug eruption along the lines of Blaschko caused by lenalidomide [in German]. Hautarzt. 2011;62:618-620. doi:10.1007/S00105-010-2121-6
- Bolognia JL, Orlow SJ, Glick SA. Lines of Blaschko. J Am Acad Dermatol. 1994;31(2 pt 1):157-190. doi:10.1016/S0190-9622(94)70143-1
To the Editor:
Lenalidomide is a thalidomide analogue used to treat various hematologic malignancies, including non-Hodgkin lymphoma, myelodysplastic syndrome, and multiple myeloma (MM).1 Lenalidomide is referred to as a degrader therapeutic because it induces targeted protein degradation of disease-relevant proteins (eg, Ikaros family zinc finger protein 1 [IKZF1], Ikaros family zinc finger protein 3 [IKZF3], and casein kinase I isoform-α [CK1α]) as its primary mechanism of action.1,2 Although cutaneous adverse events are relatively common among thalidomide analogues, the morphologic and histopathologic descriptions of these drug eruptions have not been fully elucidated.3,4 We report a novel pityriasiform drug eruption followed by a clinical eruption suggestive of blaschkitis in a patient with MM who was being treated with lenalidomide.
A 76-year-old man presented to the dermatology clinic with a progressive, mildly pruritic eruption on the chest and axillae of 1 year’s duration. He had a medical history of chronic hepatitis B, malignant carcinoid tumor of the colon, prostate cancer, and MM. The eruption emerged 1 to 2 weeks after the patient started oral lenalidomide 10 mg/d and oral dexamethasone40 mg/wk following autologous stem cell transplantation for MM. The patient had not received any other therapy for MM.
Physical examination revealed multiple erythematous, hyperpigmented, scaly papules and plaques on the lateral chest and within the axillae (Figure 1). A skin biopsy from the left axilla demonstrated a mild lichenoid and perivascular lymphocytic infiltrate with scattered eosinophils, neutrophils, and extravasated erythrocytes. The overlying epidermis showed spongiosis with parakeratosis in addition to lymphocytic exocytosis (Figure 2). No fungal organisms were highlighted on periodic acid–Schiff staining. After this evaluation, we recommended that the patient discontinue lenalidomide and start taking a topical over-the-counter corticosteroid for 2 weeks. Over time, he noted marked improvement in the eruption and associated pruritus.
After a drug holiday of 2 months, the patient resumed a maintenance dosage of oral lenalidomide 10 mg/d. Four or 5 days after restarting lenalidomide, a pruritic eruption appeared that involved the axillae and the left lower abdomen, circling around to the left lower back. The axillary eruption resolved with a topical over-the-counter corticosteroid; the abdominal eruption persisted.
At the 3-month follow-up visit, physical examination revealed erythematous macules and papules that coalesced over a salmon-colored base along the lines of Blaschko extending from the left lower abdominal quadrant, crossing the left flank, and continuing to the left lower back without crossing the midline (Figure 3).
We recommended that the patient continue treatment through this eruption; he was instructed to apply a corticosteroid cream and resume lenalidomide at the maintenance dosage. A month later, he reported that the eruption and associated pruritus resolved with the corticosteroid cream and resumption of the maintenance dose of lenalidomide. The patient noted no further spread of the eruption.
Cutaneous adverse events are common following lenalidomide. In prior trials, the overall incidence of any-grade rash following lenalidomide exposure was 22% to 33%.5 A meta-analysis of 10 trials determined the overall incidence of all-grade and high-grade cutaneous adverse events after exposure to lenalidomide was 27.2% and 3.6%, respectively.6 Our case represents a pityriasiform eruption due to lenalidomide followed by a secondary eruption suggestive of blaschkitis.
The rash due to lenalidomide has been described as morbilliform, urticarial, dermatitic, acneform, and undefined.7 Lenalidomide-induced rash typically develops during the first month of therapy, similar to our patient’s presentation. It has even been observed in the first week of therapy.8 Severe reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.5,6 Risk factors associated with rash secondary to lenalidomide include advanced age (≥70 years), presence of Bence-Jones protein-type MM in urine, and no prior chemotherapy.8 Our patient had 2 of these risk factors: advanced age and no prior chemotherapy for MM. The exact pathogenesis by which lenalidomide leads to a pityriasiform eruption, as in our patient, or to a rash in general is unclear. Studies have hypothesized that a lenalidomide-induced rash could be attributable to a delayed hypersensitivity type IV reaction or to a reaction related to the molecular mechanism of action of the drug.9
At the molecular level, the antimyeloma effects of lenalidomide include promoting degradation of transcription factors IKZF1 and IKZF3, which subsequently increases production of IL-2.1,2,9 Recombinant IL-2 has been associated with an increased incidence of rash in other cancers.9 Overexpression of programmed death 1(PD-1) and its ligand (PD-L1) has been demonstrated in MM; lenalidomide has been shown to downregulate both PD-1 and PD-L1. Patients receiving PD-1 and PD-L1 inhibitors commonly have developed rash.9 However, the association between lenalidomide and its downregulation of PD-1 and PD-L1 leading to rash has not been fully elucidated. Given the multiple malignancies in our patient—MM, prostate cancer, malignant carcinoid tumor—an underlying paraneoplastic phenomenon may be possible. Additionally, because our patient initially received dexamethasone along with lenalidomide, the manifestation of the initial pityriasiform rash may have been less severe due to the steroid use. Although our patient underwent a 2-month drug holiday following the initial pityriasiform eruption, most lenalidomide-induced rashes do not necessitate discontinuation of the drug.5,7
Our patient’s secondary drug eruption was clinically suggestive of lenalidomide-induced blaschkitis. A report of a German patient with plasmacytoma described a unilateral papular exanthem that developed 4 months after lenalidomide was initiated.10 The papular exanthem following the lines of Blaschko lines extended from that patient’s posterior left foot to the calf and on to the thigh and flank,10 which was more extensive than our patient’s eruption. Blaschkitis in this patient resolved with a corticosteroid cream and UV light therapy10; lenalidomide was not discontinued, similar to our patient.
The pathogenesis of our patient’s secondary eruption that preferentially involved the lines of Blaschko is unclear. After the initial pityriasiform eruption, the secondary eruption was blaschkitis. Distinguishing dermatomes from the lines of Blaschko, which are thought to represent pathways of epidermal cell migration and proliferation during embryologic development, is important. Genodermatoses such as incontinentia pigmenti and hypomelanosis of Ito involve the lines of Blaschko11; other disorders in the differential diagnosis of linear configurations include linear lichen planus, linear cutaneous lupus erythematosus, linear morphea, and lichen striatus.11 Notably, drug-induced blaschkitis is rare.
Cutaneous adverse reactions from thalidomide analogues are relatively common. Our case of lenalidomide-associated blaschkitis that developed following an initial pityriasiform drug eruption in a patient with MM highlights that dermatologists need to collaborate with the oncologist regarding the severity of drug eruptions to determine if the patient should continue treatment through the cutaneous eruptions or discontinue a vital medication.
To the Editor:
Lenalidomide is a thalidomide analogue used to treat various hematologic malignancies, including non-Hodgkin lymphoma, myelodysplastic syndrome, and multiple myeloma (MM).1 Lenalidomide is referred to as a degrader therapeutic because it induces targeted protein degradation of disease-relevant proteins (eg, Ikaros family zinc finger protein 1 [IKZF1], Ikaros family zinc finger protein 3 [IKZF3], and casein kinase I isoform-α [CK1α]) as its primary mechanism of action.1,2 Although cutaneous adverse events are relatively common among thalidomide analogues, the morphologic and histopathologic descriptions of these drug eruptions have not been fully elucidated.3,4 We report a novel pityriasiform drug eruption followed by a clinical eruption suggestive of blaschkitis in a patient with MM who was being treated with lenalidomide.
A 76-year-old man presented to the dermatology clinic with a progressive, mildly pruritic eruption on the chest and axillae of 1 year’s duration. He had a medical history of chronic hepatitis B, malignant carcinoid tumor of the colon, prostate cancer, and MM. The eruption emerged 1 to 2 weeks after the patient started oral lenalidomide 10 mg/d and oral dexamethasone40 mg/wk following autologous stem cell transplantation for MM. The patient had not received any other therapy for MM.
Physical examination revealed multiple erythematous, hyperpigmented, scaly papules and plaques on the lateral chest and within the axillae (Figure 1). A skin biopsy from the left axilla demonstrated a mild lichenoid and perivascular lymphocytic infiltrate with scattered eosinophils, neutrophils, and extravasated erythrocytes. The overlying epidermis showed spongiosis with parakeratosis in addition to lymphocytic exocytosis (Figure 2). No fungal organisms were highlighted on periodic acid–Schiff staining. After this evaluation, we recommended that the patient discontinue lenalidomide and start taking a topical over-the-counter corticosteroid for 2 weeks. Over time, he noted marked improvement in the eruption and associated pruritus.
After a drug holiday of 2 months, the patient resumed a maintenance dosage of oral lenalidomide 10 mg/d. Four or 5 days after restarting lenalidomide, a pruritic eruption appeared that involved the axillae and the left lower abdomen, circling around to the left lower back. The axillary eruption resolved with a topical over-the-counter corticosteroid; the abdominal eruption persisted.
At the 3-month follow-up visit, physical examination revealed erythematous macules and papules that coalesced over a salmon-colored base along the lines of Blaschko extending from the left lower abdominal quadrant, crossing the left flank, and continuing to the left lower back without crossing the midline (Figure 3).
We recommended that the patient continue treatment through this eruption; he was instructed to apply a corticosteroid cream and resume lenalidomide at the maintenance dosage. A month later, he reported that the eruption and associated pruritus resolved with the corticosteroid cream and resumption of the maintenance dose of lenalidomide. The patient noted no further spread of the eruption.
Cutaneous adverse events are common following lenalidomide. In prior trials, the overall incidence of any-grade rash following lenalidomide exposure was 22% to 33%.5 A meta-analysis of 10 trials determined the overall incidence of all-grade and high-grade cutaneous adverse events after exposure to lenalidomide was 27.2% and 3.6%, respectively.6 Our case represents a pityriasiform eruption due to lenalidomide followed by a secondary eruption suggestive of blaschkitis.
The rash due to lenalidomide has been described as morbilliform, urticarial, dermatitic, acneform, and undefined.7 Lenalidomide-induced rash typically develops during the first month of therapy, similar to our patient’s presentation. It has even been observed in the first week of therapy.8 Severe reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported.5,6 Risk factors associated with rash secondary to lenalidomide include advanced age (≥70 years), presence of Bence-Jones protein-type MM in urine, and no prior chemotherapy.8 Our patient had 2 of these risk factors: advanced age and no prior chemotherapy for MM. The exact pathogenesis by which lenalidomide leads to a pityriasiform eruption, as in our patient, or to a rash in general is unclear. Studies have hypothesized that a lenalidomide-induced rash could be attributable to a delayed hypersensitivity type IV reaction or to a reaction related to the molecular mechanism of action of the drug.9
At the molecular level, the antimyeloma effects of lenalidomide include promoting degradation of transcription factors IKZF1 and IKZF3, which subsequently increases production of IL-2.1,2,9 Recombinant IL-2 has been associated with an increased incidence of rash in other cancers.9 Overexpression of programmed death 1(PD-1) and its ligand (PD-L1) has been demonstrated in MM; lenalidomide has been shown to downregulate both PD-1 and PD-L1. Patients receiving PD-1 and PD-L1 inhibitors commonly have developed rash.9 However, the association between lenalidomide and its downregulation of PD-1 and PD-L1 leading to rash has not been fully elucidated. Given the multiple malignancies in our patient—MM, prostate cancer, malignant carcinoid tumor—an underlying paraneoplastic phenomenon may be possible. Additionally, because our patient initially received dexamethasone along with lenalidomide, the manifestation of the initial pityriasiform rash may have been less severe due to the steroid use. Although our patient underwent a 2-month drug holiday following the initial pityriasiform eruption, most lenalidomide-induced rashes do not necessitate discontinuation of the drug.5,7
Our patient’s secondary drug eruption was clinically suggestive of lenalidomide-induced blaschkitis. A report of a German patient with plasmacytoma described a unilateral papular exanthem that developed 4 months after lenalidomide was initiated.10 The papular exanthem following the lines of Blaschko lines extended from that patient’s posterior left foot to the calf and on to the thigh and flank,10 which was more extensive than our patient’s eruption. Blaschkitis in this patient resolved with a corticosteroid cream and UV light therapy10; lenalidomide was not discontinued, similar to our patient.
The pathogenesis of our patient’s secondary eruption that preferentially involved the lines of Blaschko is unclear. After the initial pityriasiform eruption, the secondary eruption was blaschkitis. Distinguishing dermatomes from the lines of Blaschko, which are thought to represent pathways of epidermal cell migration and proliferation during embryologic development, is important. Genodermatoses such as incontinentia pigmenti and hypomelanosis of Ito involve the lines of Blaschko11; other disorders in the differential diagnosis of linear configurations include linear lichen planus, linear cutaneous lupus erythematosus, linear morphea, and lichen striatus.11 Notably, drug-induced blaschkitis is rare.
Cutaneous adverse reactions from thalidomide analogues are relatively common. Our case of lenalidomide-associated blaschkitis that developed following an initial pityriasiform drug eruption in a patient with MM highlights that dermatologists need to collaborate with the oncologist regarding the severity of drug eruptions to determine if the patient should continue treatment through the cutaneous eruptions or discontinue a vital medication.
- Jan M, Sperling AS, Ebert BL. Cancer therapies based on targeted protein degradation—lessons learned with lenalidomide. Nat Rev Clin Oncol. 2021;18:401-417. doi:10.1038/s41571-021-00479-z
- Shah UA, Mailankody S. Emerging immunotherapies in multiple myeloma. BMJ. 2020;370:3176. doi:10.1136/BMJ.M3176
- Richardson PG, Blood E, Mitsiades CS, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006;108:3458-3464. doi:10.1182/BLOOD-2006-04-015909
- Benboubker L, Dimopoulos MA, Dispenzieri A, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014;371:906-917. doi:10.1056/NEJMOA1402551
- Tinsley SM, Kurtin SE, Ridgeway JA. Practical management of lenalidomide-related rash. Clin Lymphoma Myeloma Leuk. 2015;15(suppl):S64-S69. doi:10.1016/J.CLML.2015.02.008
- Nardone B, Wu S, Garden BC, et al. Risk of rash associated with lenalidomide in cancer patients: a systematic review of the literature and meta-analysis. Clin Lymphoma Myeloma Leuk. 2013;13:424-429. doi:10.1016/J.CLML.2013.03.006
- Sviggum HP, Davis MDP, Rajkumar SV, et al. Dermatologic adverse effects of lenalidomide therapy for amyloidosis and multiple myeloma. Arch Dermatol. 2006;142:1298-1302. doi:10.1001/ARCHDERM.142.10.1298
- Sugi T, Nishigami Y, Saigo H, et al. Analysis of risk factors for lenalidomide-associated skin rash in patients with multiple myeloma. Leuk Lymphoma. 2021;62:1405-1410. doi:10.1080/10428194.2021.1876867
- Barley K, He W, Agarwal S, et al. Outcomes and management of lenalidomide-associated rash in patients with multiple myeloma. Leuk Lymphoma. 2016;57:2510-2515. doi:10.3109/10428194.2016.1151507
- Grape J, Frosch P. Papular drug eruption along the lines of Blaschko caused by lenalidomide [in German]. Hautarzt. 2011;62:618-620. doi:10.1007/S00105-010-2121-6
- Bolognia JL, Orlow SJ, Glick SA. Lines of Blaschko. J Am Acad Dermatol. 1994;31(2 pt 1):157-190. doi:10.1016/S0190-9622(94)70143-1
- Jan M, Sperling AS, Ebert BL. Cancer therapies based on targeted protein degradation—lessons learned with lenalidomide. Nat Rev Clin Oncol. 2021;18:401-417. doi:10.1038/s41571-021-00479-z
- Shah UA, Mailankody S. Emerging immunotherapies in multiple myeloma. BMJ. 2020;370:3176. doi:10.1136/BMJ.M3176
- Richardson PG, Blood E, Mitsiades CS, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006;108:3458-3464. doi:10.1182/BLOOD-2006-04-015909
- Benboubker L, Dimopoulos MA, Dispenzieri A, et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014;371:906-917. doi:10.1056/NEJMOA1402551
- Tinsley SM, Kurtin SE, Ridgeway JA. Practical management of lenalidomide-related rash. Clin Lymphoma Myeloma Leuk. 2015;15(suppl):S64-S69. doi:10.1016/J.CLML.2015.02.008
- Nardone B, Wu S, Garden BC, et al. Risk of rash associated with lenalidomide in cancer patients: a systematic review of the literature and meta-analysis. Clin Lymphoma Myeloma Leuk. 2013;13:424-429. doi:10.1016/J.CLML.2013.03.006
- Sviggum HP, Davis MDP, Rajkumar SV, et al. Dermatologic adverse effects of lenalidomide therapy for amyloidosis and multiple myeloma. Arch Dermatol. 2006;142:1298-1302. doi:10.1001/ARCHDERM.142.10.1298
- Sugi T, Nishigami Y, Saigo H, et al. Analysis of risk factors for lenalidomide-associated skin rash in patients with multiple myeloma. Leuk Lymphoma. 2021;62:1405-1410. doi:10.1080/10428194.2021.1876867
- Barley K, He W, Agarwal S, et al. Outcomes and management of lenalidomide-associated rash in patients with multiple myeloma. Leuk Lymphoma. 2016;57:2510-2515. doi:10.3109/10428194.2016.1151507
- Grape J, Frosch P. Papular drug eruption along the lines of Blaschko caused by lenalidomide [in German]. Hautarzt. 2011;62:618-620. doi:10.1007/S00105-010-2121-6
- Bolognia JL, Orlow SJ, Glick SA. Lines of Blaschko. J Am Acad Dermatol. 1994;31(2 pt 1):157-190. doi:10.1016/S0190-9622(94)70143-1
Practice Points
- Dermatologists should be aware of the variety of cutaneous adverse events that can arise from the use of immunotherapeutic agents for hematologic malignancies.
- Some cutaneous reactions to immunotherapeutic medications, such as pityriasiform eruption and blaschkitis, generally are benign and may not necessitate halting an important therapy.
The Role of Toluidine Blue in Mohs Micrographic Surgery: A Systematic Review
Toluidine blue (TB), a dye with metachromatic staining properties, was developed in 1856 by William Henry Perkin.1 Metachromasia is a perceptible change in the color of staining of living tissue due to the electrochemical properties of the tissue. Tissues that contain high concentrations of ionized sulfate and phosphate groups (high concentrations of free electronegative groups) form polymeric aggregates of the basic dye solution that alter the absorbed wavelengths of light.2 The function of this characteristic is to use a single dye to highlight different structures in tissue based on their relative chemical differences.3
Toluidine blue primarily was used within the dye industry until the 1960s, when it was first used in vital staining of the oral mucosa.2 Because of the tissue absorption potential, this technique was used to detect the location of oral malignancies.4 Since then, TB has progressively been used for staining fresh frozen sections in Mohs micrographic surgery (MMS). In a 2003 survey study (N=310), 16.8% of surgeons performing MMS reported using TB in their laboratory.5 We sought to systematically review the published literature describing the uses of TB in the setting of fresh frozen sections and MMS.
Methods
We conducted a systematic search of the PubMed and Cochrane databases for articles published before December 1, 2019, to identify any relevant studies in English. Electronic searches were performed using the terms toluidine blue and Mohs or Mohs micrographic surgery. We manually checked the bibliographies of the identified articles to further identify eligible studies.
Eligibility Criteria—The inclusion criteria were articles that (1) considered TB in the context of MMS, (2) were published in peer-reviewed journals, (3) were published in English, and (4) were available as full text. Systematic reviews were excluded.
Data Extraction and Outcomes—All relevant information regarding the study characteristics, including design, level of evidence, methodologic quality of evidence, pathology examined, and outcome measures, were collected by 2 independent reviewers (T.L. and A.D.) using a predetermined data sheet. The same 2 reviewers were used for all steps of the review process, data were independently obtained, and any discrepancy was introduced for a third opinion (D.H.) and agreed upon by the majority.
Quality Assessment—The level of evidence was evaluated based on the criteria of the Oxford Centre for Evidence-Based Medicine. Two reviewers (T.L. and A.D.) graded each article included in the review.
Results
A total of 25 articles were reviewed. After the titles and abstracts were screened for relevance, 12 articles remained (Figure 1). Of these, 1 compared basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), 4 were related to BCC, 3 were related to SCC, 1 was related to microcystic adnexal carcinoma (MAC), 1 was related to primary cutaneous adenoid cystic carcinoma (PCACC), and 2 were related to technical aspects of the staining process (Table 1).
A majority of the articles included in this review were qualitative and observational in nature, describing the staining characteristics of TB. Study characteristics are summarized in Table 1.
Comment
Basal Cell Carcinoma—Toluidine blue staining characteristics help to identify BCC nests by differentiating them from hair follicles in frozen sections. The metachromatic characteristic of TB stains the inner root sheath deep blue and highlights the surrounding stromal mucin of BCC a magenta color.18,19 In hematoxylin and eosin (H&E) stains, these 2 distinct structures can be differentiated by cleft formation around tumor nests, mitotic figures, and the lack of a fibrous sheath present in BCC tumors.20 The advantages and limitations of TB staining of BCC are presented in Table 2.
Humphreys et al6 suggested a noticeable difference between H&E and TB in the staining of cellular and stromal components. The nuclear detail of tumor cells was subjectively sharper and clearer with TB staining. The staining of stromal components may provide the most assistance in locating BCC islands. Mucopolysaccharide staining may be absent in H&E but stain a deep magenta with TB. Although the presence of mucopolysaccharides does not specifically indicate a tumor, it may prompt further attention and provide an indicator for sparse and infiltrative tumor cells.6 The metachromatic stromal change may indicate a narrow tumor-free margin where additional deeper sections often reveal tumor that may warrant additional resection margin in more aggressive malignancies. In particular, sclerosing/morpheaform BCCs have been shown to induce glycosaminoglycan synthesis and are highlighted more readily with TB than with H&E when compared to surrounding tissue.21 This differentiation in staining has remained a popular reason to routinely incorporate TB into the staining of infiltrative and morpheaform variants of BCC. Additionally, stromal mast cells are believed to be more abundant in the stroma of BCC and are more readily visualized in tissue specimens stained with TB, appearing as bright purple metachromatic granules. These granules are larger than normal and are increased in number.6
The margin behavior of BCC stained with TB was further characterized by Goldberg et al,8 who coined the term setting sun sign, which may be present in sequential sections of a disappearing nodule of a BCC tumor. Stroma, inflammatory infiltrate, and mast cells produce a magenta glow surrounding BCC tumors that is reminiscent of a setting sun (Figure 2). Invasive BCC is considered variable in this presentation, primarily because of zones of cell-free fluid and edema or the second area of inflammatory cells. This unique sign may benefit the inspecting Mohs surgeon by providing a clue to an underlying process that may have residual BCC tumors. The setting sun sign also may assist in identifying exact surgical margins.8
The nasal surface has a predilection for BCC.22 The skin of the nose has numerous look-alike structures to consider for complete tumor removal and avoidance of unnecessary removal. One challenge is distinguishing follicular basaloid proliferations (FBP) from BCC, a scenario that is more common on the nose.22 When TB staining was used, the sensitivity for detecting FBP reached 100% in 34 cases reviewed by Donaldson and Weber.10 None of the cases examined showed TB metachromasia surrounding FBP, thus indicating that TB can dependably identify this benign entity. Conversely, 5% (N=279) of BCCs confirmed on H&E did not exhibit surrounding TB metachromasia. This finding is concerning regarding the specificity of TB staining for BCC, but the authors of this study suggested the possibility that these exceptions were benign “simulants” (ie, trichoepithelioma) of BCC.10
The use of TB also has been shown to be statistically beneficial in Mohs training. In a single-center, single-fellow experiment, the sensitivity and specificity of using TB for BCC were extrapolated.9 Using TB as an adjunct in deep sections showed superior sensitivity to H&E alone in identifying BCC, increasing sensitivity from 96.3% to 99.7%. In a cohort of 352 BCC excisions and frozen sections, only 1 BCC was not completely excised. If H&E only had been performed, the fellow would have missed 13 residual BCC tumors.9
Bennett and Taher7 described a case in which hyaluronic acid (HA) from a filler injection was confused with the HA surrounding BCC tumor nests. They found that when TB is used as an adjunct, the HA filler is easier to differentiate from the HA surrounding the BCC tumor nests. In frozen sections stained with TB, the HA filler appeared as an amorphous, metachromatic, reddish-purple, whereas the HA surrounding the BCC tumor nests appeared as a well-defined red. These findings were less obvious in the same sections stained with H&E alone.7
Squamous Cell Carcinoma—In early investigations, the utility of TB in identifying SCC in frozen sections was thought to be limited. The description by Humphreys and colleagues6 of staining characteristics in SCC suggested that the nuclear detail that H&E provides is more easily recognized. The deep aqua nuclear staining produced with TB was considered more difficult to observe than the cytoplasmic eosinophilia of pyknotic and keratinizing cells in H&E.6
Toluidine blue may be beneficial in providing unique staining characteristics to further detail tumors that are difficult to interpret, such as spindle cell SCC and perineural invasion of aggressive SCC. In H&E, squamous cells of spindle cell SCC (scSCC) blend into the background of inflammatory cells and can be perceptibly difficult to locate. A small cohort of 3 Mohs surgeons who routinely use H&E were surveyed on their ability to detect a proven scSCC in H&E or TB by photograph.12 All 3 were able to detect the scSCC in the TB photographs, but only 2 of 3 were able to detect it in H&E photographs. All 3 surgeons agreed that TB was preferable to H&E for this tumor type. These findings suggested that TB may be superior and preferred over H&E for visualizing tumor cells of scSCC.12 The TB staining characteristics of perineural invasion of aggressive SCC have been referred to as the perineural corona sign because of the bright magenta stain that forms around affected nerves.13 Drosou et al13 suggested that TB may enhance the diagnostic accuracy for perineural SCC.
Rare Tumors—The adjunctive use of TB with H&E has been examined in rare tumors. Published reports have highlighted its use in MMS for treating MAC and PCACC. Toluidine blue exhibits staining advantages for these tumors. It may render isolated nests and perineural invasion of MAC more easily visible on frozen section.15
Although PCACC is rare, the recurrence rate is high.23 Toluidine blue has been used with MMS to ensure complete removal and higher cure rates. The metachromatic nature of TB is advantageous in staining the HA present in these tumors. Those who have reported the use of TB for PCACC prefer it to H&E for frozen sections.14
Technical Aspects—The staining time for TB-treated slides is reduced compared to H&E staining; staining can be efficiently done in frozen sections in less than 2.5 minutes using the method shown in Table 3.17 In comparison, typical H&E staining takes 9 minutes, and older TB techniques take 7 minutes.6
Conclusion
Toluidine blue may play an important and helpful role in the successful diagnosis and treatment of particular cutaneous tumors by providing additional diagnostic information. Although surgeons performing MMS will continue using the staining protocols with which they are most comfortable, adjunctive use of TB over time may provide an additional benefit at low risk for disrupting practice efficiency or workflow. Many Mohs surgeons are accustomed to using this stain, even preferring to interpret only TB-stained slides for cutaneous malignancy. Most published studies on this topic have been observational in nature, and additional controlled trials may be warranted to determine the effects on outcomes in real-world practice.
- Culling CF, Allison TR. Cellular Pathology Technique. 4th ed. Butterworths; 1985.
- Bergeron JA, Singer M. Metachromasy: an experimental and theoretical reevaluation. J Biophys Biochem Cytol. 1958;4:433-457. doi:10.1083/jcb.4.4.433
- Epstein JB, Scully C, Spinelli J. Toluidine blue and Lugol’s iodine application in the assessment of oral malignant disease and lesions at risk of malignancy. J Oral Pathol Med. 1992;21:160-163. doi:10.1111/j.1600-0714.1992.tb00094.x
- Warnakulasuriya KA, Johnson NW. Sensitivity and specificity of OraScan (R) toluidine blue mouthrinse in the detection of oral cancer and precancer. J Oral Pathol Med. 1996;25:97-103. doi:10.1111/j.1600-0714.1996.tb00201.x
- Silapunt S, Peterson SR, Alcalay J, et al. Mohs tissue mapping and processing: a survey study. Dermatol Surg. 2003;29:1109-1112; discussion 1112.
- Humphreys TR, Nemeth A, McCrevey S, et al. A pilot study comparing toluidine blue and hematoxylin and eosin staining of basal cell and squamous cell carcinoma during Mohs surgery. Dermatol Surg. 1996;22:693-697. doi:10.1111/j.1524-4725.1996.tb00619.x
- Bennett R, Taher M. Restylane persistent for 23 months found during Mohs micrographic surgery: a source of confusion with hyaluronic acid surrounding basal cell carcinoma. Dermatol Surg. 2005;31:1366-1369. doi:10.1111/j.1524-4725.2005.31223
- Goldberg LH, Wang SQ, Kimyai-Asadi A. The setting sun sign: visualizing the margins of a basal cell carcinoma on serial frozen sections stained with toluidine blue. Dermatol Surg. 2007;33:761-763. doi:10.1111/j.1524-4725.2007.33158.x
- Tehrani H, May K, Morris A, et al. Does the dual use of toluidine blue and hematoxylin and eosin staining improve basal cell carcinoma detection by Mohs surgery trainees? Dermatol Surg. 2013;39:995-1000. doi:10.1111/dsu.12180
- Donaldson MR, Weber LA. Toluidine blue supports differentiation of folliculocentric basaloid proliferation from basal cell carcinoma on frozen sections in a small single-practice cohort. Dermatol Surg. 2017;43:1303-1306. doi:10.1097/DSS.0000000000001107
- Styperek AR, Goldberg LH, Goldschmidt LE, et al. Toluidine blue and hematoxylin and eosin stains are comparable in evaluating squamous cell carcinoma during Mohs. Dermatol Surg. 2016;42:1279-1284. doi:10.1097/DSS.0000000000000872
- Trieu D, Drosou A, Goldberg LH, et al. Detecting spindle cell squamous cell carcinomas with toluidine blue on frozen sections. Dermatol Surg. 2014;40:1259-1260. doi:10.1097/DSS.0000000000000147
- Drosou A, Trieu D, Goldberg LH, et al. The perineural corona sign: enhancing detection of perineural squamous cell carcinoma during Mohs micrographic surgery with toluidine blue stain. J Am Acad Dermatol. 2014;71:826-827. doi:10.1016/j.jaad.2014.04.076
- Chesser RS, Bertler DE, Fitzpatrick JE, et al. Primary cutaneous adenoid cystic carcinoma treated with Mohs micrographic surgery toluidine blue technique. J Dermatol Surg Oncol. 1992;18:175-176. doi:10.1111/j.1524-4725.1992.tb02794.x
- Wang SQ, Goldberg LH, Nemeth A. The merits of adding toluidine blue-stained slides in Mohs surgery in the treatment of a microcystic adnexal carcinoma. J Am Acad Dermatol. 2007;56:1067-1069. doi:10.1016/j.jaad.2007.01.008
- Chen CL, Wilson S, Afzalneia R, et al. Topical aluminum chloride and Monsel’s solution block toluidine blue staining in Mohs frozen sections: mechanism and solution. Dermatol Surg. 2019;45:1019-1025. doi:10.1097/DSS.0000000000001761
- Todd MM, Lee JW, Marks VJ. Rapid toluidine blue stain for Mohs’ micrographic surgery. Dermatol Surg. 2005;31:244-245. doi:10.1111/j.1524-4725.2005.31053
- Picoto AM, Picoto A. Technical procedures for Mohs fresh tissue surgery. J Derm Surg Oncol. 1986;12:134-138. doi:10.1111/j.1524-4725.1986.tb01442.x
- Sperling LC, Winton GB. The transverse anatomy of androgenic alopecia. J Derm Surg Oncol. 1990;16:1127-1133. doi:10.1111/j.1524 -4725.1990.tb00024.x
- Smith-Zagone MJ, Schwartz MR. Frozen section of skin specimens. Arch Pathol Lab Med. 2005;129:1536-1543. doi:10.5858/2005-129-1536-FSOSS
- Moy RL, Potter TS, Uitto J. Increased glycosaminoglycans production in sclerosing basal cell carcinoma–derived fibroblasts and stimulation of normal skin fibroblast glycosaminoglycans production by a cytokine-derived from sclerosing basal cell carcinoma. Dermatol Surg. 2000;26:1029-1036. doi:10.1046/j.1524-4725.2000.0260111029.x
- Leshin B, White WL. Folliculocentric basaloid proliferation. The bulge (der Wulst) revisited. Arch Dermatol. 1990;126:900-906. doi:10.1001/archderm.126.7.900
- Seab JA, Graham JH. Primary cutaneous adenoid cystic carcinoma.J Am Acad Dermatol. 1987;17:113-118. doi:10.1016/s0190 -9622(87)70182-0
Toluidine blue (TB), a dye with metachromatic staining properties, was developed in 1856 by William Henry Perkin.1 Metachromasia is a perceptible change in the color of staining of living tissue due to the electrochemical properties of the tissue. Tissues that contain high concentrations of ionized sulfate and phosphate groups (high concentrations of free electronegative groups) form polymeric aggregates of the basic dye solution that alter the absorbed wavelengths of light.2 The function of this characteristic is to use a single dye to highlight different structures in tissue based on their relative chemical differences.3
Toluidine blue primarily was used within the dye industry until the 1960s, when it was first used in vital staining of the oral mucosa.2 Because of the tissue absorption potential, this technique was used to detect the location of oral malignancies.4 Since then, TB has progressively been used for staining fresh frozen sections in Mohs micrographic surgery (MMS). In a 2003 survey study (N=310), 16.8% of surgeons performing MMS reported using TB in their laboratory.5 We sought to systematically review the published literature describing the uses of TB in the setting of fresh frozen sections and MMS.
Methods
We conducted a systematic search of the PubMed and Cochrane databases for articles published before December 1, 2019, to identify any relevant studies in English. Electronic searches were performed using the terms toluidine blue and Mohs or Mohs micrographic surgery. We manually checked the bibliographies of the identified articles to further identify eligible studies.
Eligibility Criteria—The inclusion criteria were articles that (1) considered TB in the context of MMS, (2) were published in peer-reviewed journals, (3) were published in English, and (4) were available as full text. Systematic reviews were excluded.
Data Extraction and Outcomes—All relevant information regarding the study characteristics, including design, level of evidence, methodologic quality of evidence, pathology examined, and outcome measures, were collected by 2 independent reviewers (T.L. and A.D.) using a predetermined data sheet. The same 2 reviewers were used for all steps of the review process, data were independently obtained, and any discrepancy was introduced for a third opinion (D.H.) and agreed upon by the majority.
Quality Assessment—The level of evidence was evaluated based on the criteria of the Oxford Centre for Evidence-Based Medicine. Two reviewers (T.L. and A.D.) graded each article included in the review.
Results
A total of 25 articles were reviewed. After the titles and abstracts were screened for relevance, 12 articles remained (Figure 1). Of these, 1 compared basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), 4 were related to BCC, 3 were related to SCC, 1 was related to microcystic adnexal carcinoma (MAC), 1 was related to primary cutaneous adenoid cystic carcinoma (PCACC), and 2 were related to technical aspects of the staining process (Table 1).
A majority of the articles included in this review were qualitative and observational in nature, describing the staining characteristics of TB. Study characteristics are summarized in Table 1.
Comment
Basal Cell Carcinoma—Toluidine blue staining characteristics help to identify BCC nests by differentiating them from hair follicles in frozen sections. The metachromatic characteristic of TB stains the inner root sheath deep blue and highlights the surrounding stromal mucin of BCC a magenta color.18,19 In hematoxylin and eosin (H&E) stains, these 2 distinct structures can be differentiated by cleft formation around tumor nests, mitotic figures, and the lack of a fibrous sheath present in BCC tumors.20 The advantages and limitations of TB staining of BCC are presented in Table 2.
Humphreys et al6 suggested a noticeable difference between H&E and TB in the staining of cellular and stromal components. The nuclear detail of tumor cells was subjectively sharper and clearer with TB staining. The staining of stromal components may provide the most assistance in locating BCC islands. Mucopolysaccharide staining may be absent in H&E but stain a deep magenta with TB. Although the presence of mucopolysaccharides does not specifically indicate a tumor, it may prompt further attention and provide an indicator for sparse and infiltrative tumor cells.6 The metachromatic stromal change may indicate a narrow tumor-free margin where additional deeper sections often reveal tumor that may warrant additional resection margin in more aggressive malignancies. In particular, sclerosing/morpheaform BCCs have been shown to induce glycosaminoglycan synthesis and are highlighted more readily with TB than with H&E when compared to surrounding tissue.21 This differentiation in staining has remained a popular reason to routinely incorporate TB into the staining of infiltrative and morpheaform variants of BCC. Additionally, stromal mast cells are believed to be more abundant in the stroma of BCC and are more readily visualized in tissue specimens stained with TB, appearing as bright purple metachromatic granules. These granules are larger than normal and are increased in number.6
The margin behavior of BCC stained with TB was further characterized by Goldberg et al,8 who coined the term setting sun sign, which may be present in sequential sections of a disappearing nodule of a BCC tumor. Stroma, inflammatory infiltrate, and mast cells produce a magenta glow surrounding BCC tumors that is reminiscent of a setting sun (Figure 2). Invasive BCC is considered variable in this presentation, primarily because of zones of cell-free fluid and edema or the second area of inflammatory cells. This unique sign may benefit the inspecting Mohs surgeon by providing a clue to an underlying process that may have residual BCC tumors. The setting sun sign also may assist in identifying exact surgical margins.8
The nasal surface has a predilection for BCC.22 The skin of the nose has numerous look-alike structures to consider for complete tumor removal and avoidance of unnecessary removal. One challenge is distinguishing follicular basaloid proliferations (FBP) from BCC, a scenario that is more common on the nose.22 When TB staining was used, the sensitivity for detecting FBP reached 100% in 34 cases reviewed by Donaldson and Weber.10 None of the cases examined showed TB metachromasia surrounding FBP, thus indicating that TB can dependably identify this benign entity. Conversely, 5% (N=279) of BCCs confirmed on H&E did not exhibit surrounding TB metachromasia. This finding is concerning regarding the specificity of TB staining for BCC, but the authors of this study suggested the possibility that these exceptions were benign “simulants” (ie, trichoepithelioma) of BCC.10
The use of TB also has been shown to be statistically beneficial in Mohs training. In a single-center, single-fellow experiment, the sensitivity and specificity of using TB for BCC were extrapolated.9 Using TB as an adjunct in deep sections showed superior sensitivity to H&E alone in identifying BCC, increasing sensitivity from 96.3% to 99.7%. In a cohort of 352 BCC excisions and frozen sections, only 1 BCC was not completely excised. If H&E only had been performed, the fellow would have missed 13 residual BCC tumors.9
Bennett and Taher7 described a case in which hyaluronic acid (HA) from a filler injection was confused with the HA surrounding BCC tumor nests. They found that when TB is used as an adjunct, the HA filler is easier to differentiate from the HA surrounding the BCC tumor nests. In frozen sections stained with TB, the HA filler appeared as an amorphous, metachromatic, reddish-purple, whereas the HA surrounding the BCC tumor nests appeared as a well-defined red. These findings were less obvious in the same sections stained with H&E alone.7
Squamous Cell Carcinoma—In early investigations, the utility of TB in identifying SCC in frozen sections was thought to be limited. The description by Humphreys and colleagues6 of staining characteristics in SCC suggested that the nuclear detail that H&E provides is more easily recognized. The deep aqua nuclear staining produced with TB was considered more difficult to observe than the cytoplasmic eosinophilia of pyknotic and keratinizing cells in H&E.6
Toluidine blue may be beneficial in providing unique staining characteristics to further detail tumors that are difficult to interpret, such as spindle cell SCC and perineural invasion of aggressive SCC. In H&E, squamous cells of spindle cell SCC (scSCC) blend into the background of inflammatory cells and can be perceptibly difficult to locate. A small cohort of 3 Mohs surgeons who routinely use H&E were surveyed on their ability to detect a proven scSCC in H&E or TB by photograph.12 All 3 were able to detect the scSCC in the TB photographs, but only 2 of 3 were able to detect it in H&E photographs. All 3 surgeons agreed that TB was preferable to H&E for this tumor type. These findings suggested that TB may be superior and preferred over H&E for visualizing tumor cells of scSCC.12 The TB staining characteristics of perineural invasion of aggressive SCC have been referred to as the perineural corona sign because of the bright magenta stain that forms around affected nerves.13 Drosou et al13 suggested that TB may enhance the diagnostic accuracy for perineural SCC.
Rare Tumors—The adjunctive use of TB with H&E has been examined in rare tumors. Published reports have highlighted its use in MMS for treating MAC and PCACC. Toluidine blue exhibits staining advantages for these tumors. It may render isolated nests and perineural invasion of MAC more easily visible on frozen section.15
Although PCACC is rare, the recurrence rate is high.23 Toluidine blue has been used with MMS to ensure complete removal and higher cure rates. The metachromatic nature of TB is advantageous in staining the HA present in these tumors. Those who have reported the use of TB for PCACC prefer it to H&E for frozen sections.14
Technical Aspects—The staining time for TB-treated slides is reduced compared to H&E staining; staining can be efficiently done in frozen sections in less than 2.5 minutes using the method shown in Table 3.17 In comparison, typical H&E staining takes 9 minutes, and older TB techniques take 7 minutes.6
Conclusion
Toluidine blue may play an important and helpful role in the successful diagnosis and treatment of particular cutaneous tumors by providing additional diagnostic information. Although surgeons performing MMS will continue using the staining protocols with which they are most comfortable, adjunctive use of TB over time may provide an additional benefit at low risk for disrupting practice efficiency or workflow. Many Mohs surgeons are accustomed to using this stain, even preferring to interpret only TB-stained slides for cutaneous malignancy. Most published studies on this topic have been observational in nature, and additional controlled trials may be warranted to determine the effects on outcomes in real-world practice.
Toluidine blue (TB), a dye with metachromatic staining properties, was developed in 1856 by William Henry Perkin.1 Metachromasia is a perceptible change in the color of staining of living tissue due to the electrochemical properties of the tissue. Tissues that contain high concentrations of ionized sulfate and phosphate groups (high concentrations of free electronegative groups) form polymeric aggregates of the basic dye solution that alter the absorbed wavelengths of light.2 The function of this characteristic is to use a single dye to highlight different structures in tissue based on their relative chemical differences.3
Toluidine blue primarily was used within the dye industry until the 1960s, when it was first used in vital staining of the oral mucosa.2 Because of the tissue absorption potential, this technique was used to detect the location of oral malignancies.4 Since then, TB has progressively been used for staining fresh frozen sections in Mohs micrographic surgery (MMS). In a 2003 survey study (N=310), 16.8% of surgeons performing MMS reported using TB in their laboratory.5 We sought to systematically review the published literature describing the uses of TB in the setting of fresh frozen sections and MMS.
Methods
We conducted a systematic search of the PubMed and Cochrane databases for articles published before December 1, 2019, to identify any relevant studies in English. Electronic searches were performed using the terms toluidine blue and Mohs or Mohs micrographic surgery. We manually checked the bibliographies of the identified articles to further identify eligible studies.
Eligibility Criteria—The inclusion criteria were articles that (1) considered TB in the context of MMS, (2) were published in peer-reviewed journals, (3) were published in English, and (4) were available as full text. Systematic reviews were excluded.
Data Extraction and Outcomes—All relevant information regarding the study characteristics, including design, level of evidence, methodologic quality of evidence, pathology examined, and outcome measures, were collected by 2 independent reviewers (T.L. and A.D.) using a predetermined data sheet. The same 2 reviewers were used for all steps of the review process, data were independently obtained, and any discrepancy was introduced for a third opinion (D.H.) and agreed upon by the majority.
Quality Assessment—The level of evidence was evaluated based on the criteria of the Oxford Centre for Evidence-Based Medicine. Two reviewers (T.L. and A.D.) graded each article included in the review.
Results
A total of 25 articles were reviewed. After the titles and abstracts were screened for relevance, 12 articles remained (Figure 1). Of these, 1 compared basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), 4 were related to BCC, 3 were related to SCC, 1 was related to microcystic adnexal carcinoma (MAC), 1 was related to primary cutaneous adenoid cystic carcinoma (PCACC), and 2 were related to technical aspects of the staining process (Table 1).
A majority of the articles included in this review were qualitative and observational in nature, describing the staining characteristics of TB. Study characteristics are summarized in Table 1.
Comment
Basal Cell Carcinoma—Toluidine blue staining characteristics help to identify BCC nests by differentiating them from hair follicles in frozen sections. The metachromatic characteristic of TB stains the inner root sheath deep blue and highlights the surrounding stromal mucin of BCC a magenta color.18,19 In hematoxylin and eosin (H&E) stains, these 2 distinct structures can be differentiated by cleft formation around tumor nests, mitotic figures, and the lack of a fibrous sheath present in BCC tumors.20 The advantages and limitations of TB staining of BCC are presented in Table 2.
Humphreys et al6 suggested a noticeable difference between H&E and TB in the staining of cellular and stromal components. The nuclear detail of tumor cells was subjectively sharper and clearer with TB staining. The staining of stromal components may provide the most assistance in locating BCC islands. Mucopolysaccharide staining may be absent in H&E but stain a deep magenta with TB. Although the presence of mucopolysaccharides does not specifically indicate a tumor, it may prompt further attention and provide an indicator for sparse and infiltrative tumor cells.6 The metachromatic stromal change may indicate a narrow tumor-free margin where additional deeper sections often reveal tumor that may warrant additional resection margin in more aggressive malignancies. In particular, sclerosing/morpheaform BCCs have been shown to induce glycosaminoglycan synthesis and are highlighted more readily with TB than with H&E when compared to surrounding tissue.21 This differentiation in staining has remained a popular reason to routinely incorporate TB into the staining of infiltrative and morpheaform variants of BCC. Additionally, stromal mast cells are believed to be more abundant in the stroma of BCC and are more readily visualized in tissue specimens stained with TB, appearing as bright purple metachromatic granules. These granules are larger than normal and are increased in number.6
The margin behavior of BCC stained with TB was further characterized by Goldberg et al,8 who coined the term setting sun sign, which may be present in sequential sections of a disappearing nodule of a BCC tumor. Stroma, inflammatory infiltrate, and mast cells produce a magenta glow surrounding BCC tumors that is reminiscent of a setting sun (Figure 2). Invasive BCC is considered variable in this presentation, primarily because of zones of cell-free fluid and edema or the second area of inflammatory cells. This unique sign may benefit the inspecting Mohs surgeon by providing a clue to an underlying process that may have residual BCC tumors. The setting sun sign also may assist in identifying exact surgical margins.8
The nasal surface has a predilection for BCC.22 The skin of the nose has numerous look-alike structures to consider for complete tumor removal and avoidance of unnecessary removal. One challenge is distinguishing follicular basaloid proliferations (FBP) from BCC, a scenario that is more common on the nose.22 When TB staining was used, the sensitivity for detecting FBP reached 100% in 34 cases reviewed by Donaldson and Weber.10 None of the cases examined showed TB metachromasia surrounding FBP, thus indicating that TB can dependably identify this benign entity. Conversely, 5% (N=279) of BCCs confirmed on H&E did not exhibit surrounding TB metachromasia. This finding is concerning regarding the specificity of TB staining for BCC, but the authors of this study suggested the possibility that these exceptions were benign “simulants” (ie, trichoepithelioma) of BCC.10
The use of TB also has been shown to be statistically beneficial in Mohs training. In a single-center, single-fellow experiment, the sensitivity and specificity of using TB for BCC were extrapolated.9 Using TB as an adjunct in deep sections showed superior sensitivity to H&E alone in identifying BCC, increasing sensitivity from 96.3% to 99.7%. In a cohort of 352 BCC excisions and frozen sections, only 1 BCC was not completely excised. If H&E only had been performed, the fellow would have missed 13 residual BCC tumors.9
Bennett and Taher7 described a case in which hyaluronic acid (HA) from a filler injection was confused with the HA surrounding BCC tumor nests. They found that when TB is used as an adjunct, the HA filler is easier to differentiate from the HA surrounding the BCC tumor nests. In frozen sections stained with TB, the HA filler appeared as an amorphous, metachromatic, reddish-purple, whereas the HA surrounding the BCC tumor nests appeared as a well-defined red. These findings were less obvious in the same sections stained with H&E alone.7
Squamous Cell Carcinoma—In early investigations, the utility of TB in identifying SCC in frozen sections was thought to be limited. The description by Humphreys and colleagues6 of staining characteristics in SCC suggested that the nuclear detail that H&E provides is more easily recognized. The deep aqua nuclear staining produced with TB was considered more difficult to observe than the cytoplasmic eosinophilia of pyknotic and keratinizing cells in H&E.6
Toluidine blue may be beneficial in providing unique staining characteristics to further detail tumors that are difficult to interpret, such as spindle cell SCC and perineural invasion of aggressive SCC. In H&E, squamous cells of spindle cell SCC (scSCC) blend into the background of inflammatory cells and can be perceptibly difficult to locate. A small cohort of 3 Mohs surgeons who routinely use H&E were surveyed on their ability to detect a proven scSCC in H&E or TB by photograph.12 All 3 were able to detect the scSCC in the TB photographs, but only 2 of 3 were able to detect it in H&E photographs. All 3 surgeons agreed that TB was preferable to H&E for this tumor type. These findings suggested that TB may be superior and preferred over H&E for visualizing tumor cells of scSCC.12 The TB staining characteristics of perineural invasion of aggressive SCC have been referred to as the perineural corona sign because of the bright magenta stain that forms around affected nerves.13 Drosou et al13 suggested that TB may enhance the diagnostic accuracy for perineural SCC.
Rare Tumors—The adjunctive use of TB with H&E has been examined in rare tumors. Published reports have highlighted its use in MMS for treating MAC and PCACC. Toluidine blue exhibits staining advantages for these tumors. It may render isolated nests and perineural invasion of MAC more easily visible on frozen section.15
Although PCACC is rare, the recurrence rate is high.23 Toluidine blue has been used with MMS to ensure complete removal and higher cure rates. The metachromatic nature of TB is advantageous in staining the HA present in these tumors. Those who have reported the use of TB for PCACC prefer it to H&E for frozen sections.14
Technical Aspects—The staining time for TB-treated slides is reduced compared to H&E staining; staining can be efficiently done in frozen sections in less than 2.5 minutes using the method shown in Table 3.17 In comparison, typical H&E staining takes 9 minutes, and older TB techniques take 7 minutes.6
Conclusion
Toluidine blue may play an important and helpful role in the successful diagnosis and treatment of particular cutaneous tumors by providing additional diagnostic information. Although surgeons performing MMS will continue using the staining protocols with which they are most comfortable, adjunctive use of TB over time may provide an additional benefit at low risk for disrupting practice efficiency or workflow. Many Mohs surgeons are accustomed to using this stain, even preferring to interpret only TB-stained slides for cutaneous malignancy. Most published studies on this topic have been observational in nature, and additional controlled trials may be warranted to determine the effects on outcomes in real-world practice.
- Culling CF, Allison TR. Cellular Pathology Technique. 4th ed. Butterworths; 1985.
- Bergeron JA, Singer M. Metachromasy: an experimental and theoretical reevaluation. J Biophys Biochem Cytol. 1958;4:433-457. doi:10.1083/jcb.4.4.433
- Epstein JB, Scully C, Spinelli J. Toluidine blue and Lugol’s iodine application in the assessment of oral malignant disease and lesions at risk of malignancy. J Oral Pathol Med. 1992;21:160-163. doi:10.1111/j.1600-0714.1992.tb00094.x
- Warnakulasuriya KA, Johnson NW. Sensitivity and specificity of OraScan (R) toluidine blue mouthrinse in the detection of oral cancer and precancer. J Oral Pathol Med. 1996;25:97-103. doi:10.1111/j.1600-0714.1996.tb00201.x
- Silapunt S, Peterson SR, Alcalay J, et al. Mohs tissue mapping and processing: a survey study. Dermatol Surg. 2003;29:1109-1112; discussion 1112.
- Humphreys TR, Nemeth A, McCrevey S, et al. A pilot study comparing toluidine blue and hematoxylin and eosin staining of basal cell and squamous cell carcinoma during Mohs surgery. Dermatol Surg. 1996;22:693-697. doi:10.1111/j.1524-4725.1996.tb00619.x
- Bennett R, Taher M. Restylane persistent for 23 months found during Mohs micrographic surgery: a source of confusion with hyaluronic acid surrounding basal cell carcinoma. Dermatol Surg. 2005;31:1366-1369. doi:10.1111/j.1524-4725.2005.31223
- Goldberg LH, Wang SQ, Kimyai-Asadi A. The setting sun sign: visualizing the margins of a basal cell carcinoma on serial frozen sections stained with toluidine blue. Dermatol Surg. 2007;33:761-763. doi:10.1111/j.1524-4725.2007.33158.x
- Tehrani H, May K, Morris A, et al. Does the dual use of toluidine blue and hematoxylin and eosin staining improve basal cell carcinoma detection by Mohs surgery trainees? Dermatol Surg. 2013;39:995-1000. doi:10.1111/dsu.12180
- Donaldson MR, Weber LA. Toluidine blue supports differentiation of folliculocentric basaloid proliferation from basal cell carcinoma on frozen sections in a small single-practice cohort. Dermatol Surg. 2017;43:1303-1306. doi:10.1097/DSS.0000000000001107
- Styperek AR, Goldberg LH, Goldschmidt LE, et al. Toluidine blue and hematoxylin and eosin stains are comparable in evaluating squamous cell carcinoma during Mohs. Dermatol Surg. 2016;42:1279-1284. doi:10.1097/DSS.0000000000000872
- Trieu D, Drosou A, Goldberg LH, et al. Detecting spindle cell squamous cell carcinomas with toluidine blue on frozen sections. Dermatol Surg. 2014;40:1259-1260. doi:10.1097/DSS.0000000000000147
- Drosou A, Trieu D, Goldberg LH, et al. The perineural corona sign: enhancing detection of perineural squamous cell carcinoma during Mohs micrographic surgery with toluidine blue stain. J Am Acad Dermatol. 2014;71:826-827. doi:10.1016/j.jaad.2014.04.076
- Chesser RS, Bertler DE, Fitzpatrick JE, et al. Primary cutaneous adenoid cystic carcinoma treated with Mohs micrographic surgery toluidine blue technique. J Dermatol Surg Oncol. 1992;18:175-176. doi:10.1111/j.1524-4725.1992.tb02794.x
- Wang SQ, Goldberg LH, Nemeth A. The merits of adding toluidine blue-stained slides in Mohs surgery in the treatment of a microcystic adnexal carcinoma. J Am Acad Dermatol. 2007;56:1067-1069. doi:10.1016/j.jaad.2007.01.008
- Chen CL, Wilson S, Afzalneia R, et al. Topical aluminum chloride and Monsel’s solution block toluidine blue staining in Mohs frozen sections: mechanism and solution. Dermatol Surg. 2019;45:1019-1025. doi:10.1097/DSS.0000000000001761
- Todd MM, Lee JW, Marks VJ. Rapid toluidine blue stain for Mohs’ micrographic surgery. Dermatol Surg. 2005;31:244-245. doi:10.1111/j.1524-4725.2005.31053
- Picoto AM, Picoto A. Technical procedures for Mohs fresh tissue surgery. J Derm Surg Oncol. 1986;12:134-138. doi:10.1111/j.1524-4725.1986.tb01442.x
- Sperling LC, Winton GB. The transverse anatomy of androgenic alopecia. J Derm Surg Oncol. 1990;16:1127-1133. doi:10.1111/j.1524 -4725.1990.tb00024.x
- Smith-Zagone MJ, Schwartz MR. Frozen section of skin specimens. Arch Pathol Lab Med. 2005;129:1536-1543. doi:10.5858/2005-129-1536-FSOSS
- Moy RL, Potter TS, Uitto J. Increased glycosaminoglycans production in sclerosing basal cell carcinoma–derived fibroblasts and stimulation of normal skin fibroblast glycosaminoglycans production by a cytokine-derived from sclerosing basal cell carcinoma. Dermatol Surg. 2000;26:1029-1036. doi:10.1046/j.1524-4725.2000.0260111029.x
- Leshin B, White WL. Folliculocentric basaloid proliferation. The bulge (der Wulst) revisited. Arch Dermatol. 1990;126:900-906. doi:10.1001/archderm.126.7.900
- Seab JA, Graham JH. Primary cutaneous adenoid cystic carcinoma.J Am Acad Dermatol. 1987;17:113-118. doi:10.1016/s0190 -9622(87)70182-0
- Culling CF, Allison TR. Cellular Pathology Technique. 4th ed. Butterworths; 1985.
- Bergeron JA, Singer M. Metachromasy: an experimental and theoretical reevaluation. J Biophys Biochem Cytol. 1958;4:433-457. doi:10.1083/jcb.4.4.433
- Epstein JB, Scully C, Spinelli J. Toluidine blue and Lugol’s iodine application in the assessment of oral malignant disease and lesions at risk of malignancy. J Oral Pathol Med. 1992;21:160-163. doi:10.1111/j.1600-0714.1992.tb00094.x
- Warnakulasuriya KA, Johnson NW. Sensitivity and specificity of OraScan (R) toluidine blue mouthrinse in the detection of oral cancer and precancer. J Oral Pathol Med. 1996;25:97-103. doi:10.1111/j.1600-0714.1996.tb00201.x
- Silapunt S, Peterson SR, Alcalay J, et al. Mohs tissue mapping and processing: a survey study. Dermatol Surg. 2003;29:1109-1112; discussion 1112.
- Humphreys TR, Nemeth A, McCrevey S, et al. A pilot study comparing toluidine blue and hematoxylin and eosin staining of basal cell and squamous cell carcinoma during Mohs surgery. Dermatol Surg. 1996;22:693-697. doi:10.1111/j.1524-4725.1996.tb00619.x
- Bennett R, Taher M. Restylane persistent for 23 months found during Mohs micrographic surgery: a source of confusion with hyaluronic acid surrounding basal cell carcinoma. Dermatol Surg. 2005;31:1366-1369. doi:10.1111/j.1524-4725.2005.31223
- Goldberg LH, Wang SQ, Kimyai-Asadi A. The setting sun sign: visualizing the margins of a basal cell carcinoma on serial frozen sections stained with toluidine blue. Dermatol Surg. 2007;33:761-763. doi:10.1111/j.1524-4725.2007.33158.x
- Tehrani H, May K, Morris A, et al. Does the dual use of toluidine blue and hematoxylin and eosin staining improve basal cell carcinoma detection by Mohs surgery trainees? Dermatol Surg. 2013;39:995-1000. doi:10.1111/dsu.12180
- Donaldson MR, Weber LA. Toluidine blue supports differentiation of folliculocentric basaloid proliferation from basal cell carcinoma on frozen sections in a small single-practice cohort. Dermatol Surg. 2017;43:1303-1306. doi:10.1097/DSS.0000000000001107
- Styperek AR, Goldberg LH, Goldschmidt LE, et al. Toluidine blue and hematoxylin and eosin stains are comparable in evaluating squamous cell carcinoma during Mohs. Dermatol Surg. 2016;42:1279-1284. doi:10.1097/DSS.0000000000000872
- Trieu D, Drosou A, Goldberg LH, et al. Detecting spindle cell squamous cell carcinomas with toluidine blue on frozen sections. Dermatol Surg. 2014;40:1259-1260. doi:10.1097/DSS.0000000000000147
- Drosou A, Trieu D, Goldberg LH, et al. The perineural corona sign: enhancing detection of perineural squamous cell carcinoma during Mohs micrographic surgery with toluidine blue stain. J Am Acad Dermatol. 2014;71:826-827. doi:10.1016/j.jaad.2014.04.076
- Chesser RS, Bertler DE, Fitzpatrick JE, et al. Primary cutaneous adenoid cystic carcinoma treated with Mohs micrographic surgery toluidine blue technique. J Dermatol Surg Oncol. 1992;18:175-176. doi:10.1111/j.1524-4725.1992.tb02794.x
- Wang SQ, Goldberg LH, Nemeth A. The merits of adding toluidine blue-stained slides in Mohs surgery in the treatment of a microcystic adnexal carcinoma. J Am Acad Dermatol. 2007;56:1067-1069. doi:10.1016/j.jaad.2007.01.008
- Chen CL, Wilson S, Afzalneia R, et al. Topical aluminum chloride and Monsel’s solution block toluidine blue staining in Mohs frozen sections: mechanism and solution. Dermatol Surg. 2019;45:1019-1025. doi:10.1097/DSS.0000000000001761
- Todd MM, Lee JW, Marks VJ. Rapid toluidine blue stain for Mohs’ micrographic surgery. Dermatol Surg. 2005;31:244-245. doi:10.1111/j.1524-4725.2005.31053
- Picoto AM, Picoto A. Technical procedures for Mohs fresh tissue surgery. J Derm Surg Oncol. 1986;12:134-138. doi:10.1111/j.1524-4725.1986.tb01442.x
- Sperling LC, Winton GB. The transverse anatomy of androgenic alopecia. J Derm Surg Oncol. 1990;16:1127-1133. doi:10.1111/j.1524 -4725.1990.tb00024.x
- Smith-Zagone MJ, Schwartz MR. Frozen section of skin specimens. Arch Pathol Lab Med. 2005;129:1536-1543. doi:10.5858/2005-129-1536-FSOSS
- Moy RL, Potter TS, Uitto J. Increased glycosaminoglycans production in sclerosing basal cell carcinoma–derived fibroblasts and stimulation of normal skin fibroblast glycosaminoglycans production by a cytokine-derived from sclerosing basal cell carcinoma. Dermatol Surg. 2000;26:1029-1036. doi:10.1046/j.1524-4725.2000.0260111029.x
- Leshin B, White WL. Folliculocentric basaloid proliferation. The bulge (der Wulst) revisited. Arch Dermatol. 1990;126:900-906. doi:10.1001/archderm.126.7.900
- Seab JA, Graham JH. Primary cutaneous adenoid cystic carcinoma.J Am Acad Dermatol. 1987;17:113-118. doi:10.1016/s0190 -9622(87)70182-0
Practice Points
- Toluidine blue (TB) staining can be integrated into Mohs micrographic surgery (MMS) for enhanced diagnosis of cutaneous tumors. Its metachromatic properties can aid in differentiating tumor cells from surrounding tissues, especially in basal cell carcinomas and squamous cell carcinomas.
- It is important to develop expertise in interpreting TB-stained sections, as it may offer clearer visualization of nuclear details and stromal components, potentially leading to more accurate diagnosis and effective tumor margin identification.
- Toluidine blue staining can be incorporated into routine MMS practice considering its quick staining process and low disruption to workflow. This can potentially improve diagnostic efficiency without significantly lengthening surgery time.
Reactive Angioendotheliomatosis Following Ad26.COV2.S Vaccination
To the Editor:
Reactive angioendotheliomatosis (RAE) is a rare self-limited cutaneous vascular proliferation of endothelial cells within blood vessels that manifests clinically as infiltrated red-blue patches and plaques with purpura that can progress to occlude vascular lumina. The etiology of RAE is mostly idiopathic; however, the disorder typically occurs in association with a range of systemic diseases, including infection, cryoglobulinemia, leukemia, antiphospholipid syndrome, peripheral vascular disease, and arteriovenous fistula. Histopathologic examination of these lesions shows marked proliferation of endothelial cells, including occlusion of the lumen of blood vessels over wide areas.
After ruling out malignancy, treatment of RAE focuses on targeting the underlying cause or disease, if any is present; 75% of reported cases occur in association with systemic disease.1 Onset can occur at any age without predilection for sex. Reactive angioendotheliomatosis commonly manifests on the extremities but may occur on the head and neck in rare instances.2
The rarity of the condition and its poorly defined clinical characteristics make it difficult to develop a treatment plan. There are no standardized treatment guidelines for the reactive form of angiomatosis. We report a case of RAE that developed 2 weeks after vaccination with the Ad26.COV2.S vaccine (Johnson & Johnson Innovative Medicine [formerly Janssen Pharmaceutical Companies of Johnson & Johnson]) that improved following 2 weeks of treatment with a topical corticosteroid and an oral antihistamine.
A 58-year-old man presented to an outpatient dermatology clinic with pruritus and occasional paresthesia associated with a rash over the left arm of 1 month’s duration. The patient suspected that the rash may have formed secondary to the bite of oak mites on the arms and chest while he was carrying milled wood. Further inquiry into the patient’s history revealed that he received the Ad26.COV2.S vaccine 2 weeks prior to the appearance of the rash. He denied mechanical trauma. His medical history included hypercholesterolemia and a mild COVID-19 infection 8 months prior to the appearance of the rash that did not require hospitalization. He denied fever or chills during the 2 weeks following vaccination. The pruritus was minimally relieved for short periods with over-the-counter calamine lotion. The patient’s medication regimen included daily pravastatin and loratadine at the time of the initial visit. He used acetaminophen as needed for knee pain.
Physical examination revealed palpable purpura in a dermatomal distribution with nonpitting edema over the left scapula (Figure 1A), left anterolateral shoulder, left lateral volar forearm, and thenar eminence of the left hand (Figure 1B). Notably, the entire right arm, conjunctivae, tongue, lips, and bilateral fingernails were clear. Three 4-mm punch biopsies were performed at the initial presentation: 1 perilesional biopsy for direct immunofluorescence testing and 2 lesional biopsies for routine histologic evaluation. An extensive serologic workup failed to reveal abnormalities. An activated partial thromboplastin time, dilute Russell viper venom time, serum protein electrophoresis, and levels of rheumatoid factor and angiotensin-converting enzyme were within reference range. Anticardiolipin antibodies IgA, IgM, and IgG were negative. A cryoglobulin test was negative.
Histopathology revealed a proliferation of irregularly shaped vascular spaces with plump endothelium in the papillary dermis (Figure 2). Scattered leukocyte common antigen-positive lymphocytes were noted within lesions. The epidermis appeared normal, without evidence of spongiosis or alteration of the stratum corneum. Immunohistochemical studies of the perilesional skin biopsy revealed positivity for CD31 and D2-40 (Figure 3). Specimens were negative for CD20 and human herpesvirus 8. Direct immunofluorescence of the perilesional biopsy was negative.
A diagnosis of RAE was made based on clinical and histologic findings. Treatment with triamcinolone ointment 0.1% twice daily and oral cetirizine 10 mg twice daily was initiated. Re-evaluation 2 weeks later revealed notable improvement in the affected areas, including decreased edema, improvement of the purpura, and absence of pruritus. The patient noted no further spread or blister formation while the active areas were being treated with the topical steroid. The treatment regimen was modified to triamcinolone ointment 0.1% once daily, and cetirizine was discontinued. At 3-month follow-up, active areas had completely resolved (Figure 4) and triamcinolone was discontinued. To date, the patient has not had recurrence of symptoms and remains healthy.
Gottron and Nikolowski3 reported the first case of RAE in an adult patient who presented with purpuric patches secondary to skin infarction. Current definitions use the umbrella term cutaneous reactive angiomatosis to cover 3 major subtypes: reactive angioendotheliomatosis, diffuse dermal angioendotheliomatosis, and acroangiodermatitis (pseudo-Kaposi sarcoma [KS]). The manifestation of these subgroups is clinically similar, and they must be differentiated through histologic evaluation.4
Reactive angioendotheliomatosis has an unknown pathogenesis and is poorly defined clinically. The exact pathophysiology is unknown but likely is linked to vaso-occlusion and hypoxia.1 A PubMed search of articles indexed for MEDLINE, as well as a review of Science Direct, Google Scholar, and Cochrane Library, using the terms reactive angioendotheliomatosis, COVID, vaccine, Ad26.COV2.S, and RAE in any combination revealed no prior cases of RAE in association with Ad26.COV2.S vaccination.
By the late 1980s, systemic angioendotheliomatosis was segregated into 2 distinct entities: malignant and reactive.4 The differential diagnosis of malignant systemic angioendotheliomatosis includes KS and angiosarcoma; nonmalignant causes are the variants of cutaneous reactive angiomatosis. It is important to rule out KS because of its malignant and deceptive nature. It is unknown if KS originates in blood vessels or lymphatic endothelial cells; however, evidence is strongly in favor of blood vessel origin using CD31 and CD34 endothelial markers.5 CD34 positivity is more reliable than CD31 in diagnosing KS, but the absence of both markers does not offer enough evidence to rule out KS on its own.6
In our patient, histopathology revealed cells positive for CD31 and D2-40; the latter is a lymphatic endothelial cell marker that stains the endothelium of lymphatic channels but not blood vessels.7 Positive D2-40 can be indicative of KS and non-KS lesions, each with a distinct staining pattern. D2-40 staining on non-KS lesions is confined to lymphatic vessels, as it was in our patient; in contrast, spindle-shaped cells also will be stained in KS lesions.8
Another cell marker, CD20, is a B cell–specific protein that can be measured to help diagnose malignant diseases such as B-cell lymphoma and leukemia. Human herpesvirus 8 (also known as KS-associated herpesvirus) is the infectious cause of KS and traditionally has been detected using methods such as the polymerase chain reaction.9,10
Most cases of RAE are idiopathic and occur in association with systemic disease, which was not the case in our patient. We speculated that his reaction was most likely triggered by vascular transfection of endothelial cells secondary to Ad26.COV2.S vaccination. Alternatively, vaccination may have caused vascular occlusion, though the lack of cyanosis, nail changes, and route of inoculant make this less likely.
All approved COVID-19 vaccines are designed solely for intramuscular injection. In comparison to other types of tissue, muscles have superior vascularity, allowing for enhanced mobilization of compounds, which results in faster systemic circulation.11 Alternative methods of injection, including intravascular, subcutaneous, and intradermal, may lead to decreased efficacy or adverse events, or both.
Prior cases of RAE have been treated with laser therapy, topical or systemic corticosteroids, excisional removal, or topical β-blockers, such as timolol.12β-Blocking agents act on β-adrenergic receptors on endothelial cells to inhibit angiogenesis by reducing release of blood vessel growth-signaling molecules and triggering apoptosis. In this patient, topical steroids and oral antihistamines were sufficient treatment.
Vaccine-related adverse events have been reported but remain rare. The benefits of Ad26.COV2.S vaccination for protection against COVID-19 outweigh the extremely low risk for adverse events.13 For that reason, the Centers for Disease Control and Prevention recommends a booster for individuals who are eligible to maximize protection. Intramuscular injection of Ad26.COV2.S resulted in a lower incidence of moderate to severe COVID-19 cases in all age groups vs the placebo group. Hypersensitivity adverse events were reported in 0.4% of Ad26.COV2.S-vaccinated patients vs 0.4% of patients who received a placebo; the more common reactions were nonanaphylactic.13
There have been 12 reports of cerebral venous sinus thrombosis with thrombocytopenia after Ad26.COV2.S vaccination, which sparked nationwide controversy over the safety of the Ad26.COV2.S vaccine.14 After further investigation into those reports, the US Food and Drug Administration and the Centers for Disease Control and Prevention concluded that the benefits of the Ad26.COV2.S vaccine outweigh the low risk for associated thrombosis.15
Although adverse reactions are rare, it is important that health care providers take proper safety measures before and while administering any COVID-19 vaccine. Patients should be screened for contraindications to the COVID-19 vaccine to mitigate adverse effects seen in the small percentage of patients who may need to take alternative precautions.
The broad tissue tropism and high transmissibility of SARS-CoV-2 are the main contributors to its infection having reached pandemic scale. The spike (S) protein on SARS-CoV-2 binds to ACE2, the most thoroughly studied SARS-CoV-2 receptor, which is found in a range of tissues, including arterial endothelial cells, leading to its transfection. Several studies have proposed that expression of the S protein causes endothelial dysfunction through cytokine release, activation of complement, and ultimately microvascular occlusion.16
Recent developments in the use of viral-like particles, such as vesicular stomatitis virus, may mitigate future cases of RAE that are associated with endothelial cell transfection. Vesicular stomatitis virus is a popular model virus for research applications due to its glycoprotein and matrix protein contributing to its broad tropism. Recent efforts to alter these proteins have successfully limited the broad tropism of vesicular stomatitis virus.17
The SARS-CoV-2 virus must be handled in a Biosafety Level 3 laboratory. Conversely, pseudoviruses can be handled in lower containment facilities due to their safe and efficacious nature, offering an avenue to expedite vaccine development against many viral outbreaks, including SARS-CoV-2.18
An increasing number of cutaneous manifestations have been associated with COVID-19 infection and vaccination. Eruptive pseudoangiomatosis, a rare self-limiting exanthem, has been reported in association with COVID-19 vaccination.19 Eruptive pseudoangiomatosis manifests as erythematous blanchable papules that resemble angiomas, typically in a widespread distribution. Eruptive pseudoangiomatosis has striking similarities to RAE histologically; both manifest as dilated dermal blood vessels with plump endothelial cells.
Our case is unique because of the vasculitic palpable nature of the lesions, which were localized to the left arm. Eruptive pseudoangiomatosis formation after COVID-19 infection or SARS-CoV-2 vaccination may suggest alteration of ACE2 by binding of S protein.20 Such alteration of the ACE2 pathway would lead to inflammation of angiotensin II, causing proliferation of endothelial cells in the formation of angiomalike lesions. This hypothesis suggests a paraviral eruption secondary to an immunologic reaction, not a classical virtual eruption from direct contact of the virus on blood vessels. Although EPA and RAE are harmless and self-limiting, these reports will spread awareness of the increasing number of skin manifestations related to COVID-19 and SARS-CoV-2 virus vaccination.
Acknowledgment—Thoughtful insights and comments on this manuscript were provided by Christine J. Ko, MD (New Haven, Connecticut); Christine L. Egan, MD (Glen Mills, Pennsylvania); Howard A. Bueller, MD (Delray Beach, Florida); and Juan Pablo Robles, PhD (Juriquilla, Mexico).
- McMenamin ME, Fletcher CDM. Reactive angioendotheliomatosis: a study of 15 cases demonstrating a wide clinicopathologic spectrum. Am J Surg Pathol. 2002;26:686-697. doi:10.1097/00000478-200206000-00001
- Khan S, Pujani M, Jetley S, et al. Angiomatosis: a rare vascular proliferation of head and neck region. J Cutan Aesthet Surg. 2015;8:108-110. doi:10.4103/0974-2077.158448
- Gottron HA, Nikolowski W. Extrarenal Lohlein focal nephritis of the skin in endocarditis. Arch Klin Exp Dermatol. 1958;207:156-176.
- Cooper PH. Angioendotheliomatosis: two separate diseases. J Cutan Pathol. 1988;15:259. doi:10.1111/j.1600-0560.1988.tb00556.x
- Cancian L, Hansen A, Boshoff C. Cellular origin of Kaposi’s sarcoma and Kaposi’s sarcoma-associated herpesvirus-induced cell reprogramming. Trends Cell Biol. Sep 2013;23:421-32. doi:10.1016/j.tcb.2013.04.001
- Russell Jones R, Orchard G, Zelger B, et al. Immunostaining for CD31 and CD34 in Kaposi sarcoma. J Clin Pathol. 1995;48:1011-1016. doi:10.1136/jcp.48.11.1011
- Kahn HJ, Bailey D, Marks A. Monoclonal antibody D2-40, a new marker of lymphatic endothelium, reacts with Kaposi’s sarcoma and a subset of angiosarcomas. Mod Pathol. 2002;15:434-440. doi:10.1038/modpathol.3880543
- Genedy RM, Hamza AM, Abdel Latef AA, et al. Sensitivity and specificity of D2-40 in differentiating Kaposi sarcoma from its mimickers. J Egyptian Womens Dermatolog Soc. 2021;18:67-74. doi:10.4103/jewd.jewd_61_20
- Mesri EA, Cesarman E, Boshoff C. Kaposi’s sarcoma and its associated herpesvirus. Nat Rev Cancer. 2010;10:707-719. doi:10.1038/nrc2888
- Patel RM, Goldblum JR, Hsi ED. Immunohistochemical detection of human herpes virus-8 latent nuclear antigen-1 is useful in the diagnosis of Kaposi sarcoma. Mod Pathol. 2004;17:456-460. doi:10.1038/modpathol.3800061
- Zuckerman JN. The importance of injecting vaccines into muscle. Different patients need different needle sizes. BMJ. 2000;321:1237-1238. doi:10.1136/bmj.321.7271.1237
- Bhatia R, Hazarika N, Chandrasekaran D, et al. Treatment of posttraumatic reactive angioendotheliomatosis with topical timolol maleate. JAMA Dermatol. 2021;157:1002-1004. doi:10.1001/jamadermatol.2021.1770
- Sadoff J, Gray G, Vandebosch A, et al; ENSEMBLE Study Group. Safety and efficacy of single-dose Ad26.COV2.S vaccine against Covid-19. N Engl J Med. 2021;384:2187-2201. doi:10.1056/NEJMoa2101544
- See I, Su JR, Lale A, et al. US case reports of cerebral venous sinus thrombosis with thrombocytopenia after Ad26.COV2.S vaccination, March 2 to April 21, 2021. JAMA. 2021;325:2448-2456. doi:10.1001/jama.2021.7517
- Berry CT, Eliliwi M, Gallagher S, et al. Cutaneous small vessel vasculitis following single-dose Janssen Ad26.COV2.S vaccination. JAAD Case Rep. 2021;15:11-14. doi:10.1016/j.jdcr.2021.07.002
- Flaumenhaft R, Enjyoji K, Schmaier AA. Vasculopathy in COVID-19. Blood. 2022;140:222-235. doi:10.1182/blood.2021012250
- Hastie E, Cataldi M, Marriott I, et al. Understanding and altering cell tropism of vesicular stomatitis virus. Virus Res. 2013;176:16-32. doi:10.1016/j.virusres.2013.06.003
- Xiong H-L, Wu Y-T, Cao J-L, et al. Robust neutralization assay based on SARS-CoV-2 S-protein-bearing vesicular stomatitis virus (VSV) pseudovirus and ACE2-overexpressing BHK21 cells. Emerg Microbes Infect. 2020;9:2105-2113. doi:10.1080/22221751.2020.1815589
- Mohta A, Jain SK, Mehta RD, et al. Development of eruptive pseudoangiomatosis following COVID-19 immunization – apropos of 5 cases. J Eur Acad Dermatol Venereol. 2021;35:e722-e725. doi:10.1111/jdv.17499
- Angeli F, Spanevello A, Reboldi G, et al. SARS-CoV-2 vaccines: lights and shadows. Eur J Intern Med. 2021;88:1-8. doi:10.1016/j.ejim.2021.04.019
To the Editor:
Reactive angioendotheliomatosis (RAE) is a rare self-limited cutaneous vascular proliferation of endothelial cells within blood vessels that manifests clinically as infiltrated red-blue patches and plaques with purpura that can progress to occlude vascular lumina. The etiology of RAE is mostly idiopathic; however, the disorder typically occurs in association with a range of systemic diseases, including infection, cryoglobulinemia, leukemia, antiphospholipid syndrome, peripheral vascular disease, and arteriovenous fistula. Histopathologic examination of these lesions shows marked proliferation of endothelial cells, including occlusion of the lumen of blood vessels over wide areas.
After ruling out malignancy, treatment of RAE focuses on targeting the underlying cause or disease, if any is present; 75% of reported cases occur in association with systemic disease.1 Onset can occur at any age without predilection for sex. Reactive angioendotheliomatosis commonly manifests on the extremities but may occur on the head and neck in rare instances.2
The rarity of the condition and its poorly defined clinical characteristics make it difficult to develop a treatment plan. There are no standardized treatment guidelines for the reactive form of angiomatosis. We report a case of RAE that developed 2 weeks after vaccination with the Ad26.COV2.S vaccine (Johnson & Johnson Innovative Medicine [formerly Janssen Pharmaceutical Companies of Johnson & Johnson]) that improved following 2 weeks of treatment with a topical corticosteroid and an oral antihistamine.
A 58-year-old man presented to an outpatient dermatology clinic with pruritus and occasional paresthesia associated with a rash over the left arm of 1 month’s duration. The patient suspected that the rash may have formed secondary to the bite of oak mites on the arms and chest while he was carrying milled wood. Further inquiry into the patient’s history revealed that he received the Ad26.COV2.S vaccine 2 weeks prior to the appearance of the rash. He denied mechanical trauma. His medical history included hypercholesterolemia and a mild COVID-19 infection 8 months prior to the appearance of the rash that did not require hospitalization. He denied fever or chills during the 2 weeks following vaccination. The pruritus was minimally relieved for short periods with over-the-counter calamine lotion. The patient’s medication regimen included daily pravastatin and loratadine at the time of the initial visit. He used acetaminophen as needed for knee pain.
Physical examination revealed palpable purpura in a dermatomal distribution with nonpitting edema over the left scapula (Figure 1A), left anterolateral shoulder, left lateral volar forearm, and thenar eminence of the left hand (Figure 1B). Notably, the entire right arm, conjunctivae, tongue, lips, and bilateral fingernails were clear. Three 4-mm punch biopsies were performed at the initial presentation: 1 perilesional biopsy for direct immunofluorescence testing and 2 lesional biopsies for routine histologic evaluation. An extensive serologic workup failed to reveal abnormalities. An activated partial thromboplastin time, dilute Russell viper venom time, serum protein electrophoresis, and levels of rheumatoid factor and angiotensin-converting enzyme were within reference range. Anticardiolipin antibodies IgA, IgM, and IgG were negative. A cryoglobulin test was negative.
Histopathology revealed a proliferation of irregularly shaped vascular spaces with plump endothelium in the papillary dermis (Figure 2). Scattered leukocyte common antigen-positive lymphocytes were noted within lesions. The epidermis appeared normal, without evidence of spongiosis or alteration of the stratum corneum. Immunohistochemical studies of the perilesional skin biopsy revealed positivity for CD31 and D2-40 (Figure 3). Specimens were negative for CD20 and human herpesvirus 8. Direct immunofluorescence of the perilesional biopsy was negative.
A diagnosis of RAE was made based on clinical and histologic findings. Treatment with triamcinolone ointment 0.1% twice daily and oral cetirizine 10 mg twice daily was initiated. Re-evaluation 2 weeks later revealed notable improvement in the affected areas, including decreased edema, improvement of the purpura, and absence of pruritus. The patient noted no further spread or blister formation while the active areas were being treated with the topical steroid. The treatment regimen was modified to triamcinolone ointment 0.1% once daily, and cetirizine was discontinued. At 3-month follow-up, active areas had completely resolved (Figure 4) and triamcinolone was discontinued. To date, the patient has not had recurrence of symptoms and remains healthy.
Gottron and Nikolowski3 reported the first case of RAE in an adult patient who presented with purpuric patches secondary to skin infarction. Current definitions use the umbrella term cutaneous reactive angiomatosis to cover 3 major subtypes: reactive angioendotheliomatosis, diffuse dermal angioendotheliomatosis, and acroangiodermatitis (pseudo-Kaposi sarcoma [KS]). The manifestation of these subgroups is clinically similar, and they must be differentiated through histologic evaluation.4
Reactive angioendotheliomatosis has an unknown pathogenesis and is poorly defined clinically. The exact pathophysiology is unknown but likely is linked to vaso-occlusion and hypoxia.1 A PubMed search of articles indexed for MEDLINE, as well as a review of Science Direct, Google Scholar, and Cochrane Library, using the terms reactive angioendotheliomatosis, COVID, vaccine, Ad26.COV2.S, and RAE in any combination revealed no prior cases of RAE in association with Ad26.COV2.S vaccination.
By the late 1980s, systemic angioendotheliomatosis was segregated into 2 distinct entities: malignant and reactive.4 The differential diagnosis of malignant systemic angioendotheliomatosis includes KS and angiosarcoma; nonmalignant causes are the variants of cutaneous reactive angiomatosis. It is important to rule out KS because of its malignant and deceptive nature. It is unknown if KS originates in blood vessels or lymphatic endothelial cells; however, evidence is strongly in favor of blood vessel origin using CD31 and CD34 endothelial markers.5 CD34 positivity is more reliable than CD31 in diagnosing KS, but the absence of both markers does not offer enough evidence to rule out KS on its own.6
In our patient, histopathology revealed cells positive for CD31 and D2-40; the latter is a lymphatic endothelial cell marker that stains the endothelium of lymphatic channels but not blood vessels.7 Positive D2-40 can be indicative of KS and non-KS lesions, each with a distinct staining pattern. D2-40 staining on non-KS lesions is confined to lymphatic vessels, as it was in our patient; in contrast, spindle-shaped cells also will be stained in KS lesions.8
Another cell marker, CD20, is a B cell–specific protein that can be measured to help diagnose malignant diseases such as B-cell lymphoma and leukemia. Human herpesvirus 8 (also known as KS-associated herpesvirus) is the infectious cause of KS and traditionally has been detected using methods such as the polymerase chain reaction.9,10
Most cases of RAE are idiopathic and occur in association with systemic disease, which was not the case in our patient. We speculated that his reaction was most likely triggered by vascular transfection of endothelial cells secondary to Ad26.COV2.S vaccination. Alternatively, vaccination may have caused vascular occlusion, though the lack of cyanosis, nail changes, and route of inoculant make this less likely.
All approved COVID-19 vaccines are designed solely for intramuscular injection. In comparison to other types of tissue, muscles have superior vascularity, allowing for enhanced mobilization of compounds, which results in faster systemic circulation.11 Alternative methods of injection, including intravascular, subcutaneous, and intradermal, may lead to decreased efficacy or adverse events, or both.
Prior cases of RAE have been treated with laser therapy, topical or systemic corticosteroids, excisional removal, or topical β-blockers, such as timolol.12β-Blocking agents act on β-adrenergic receptors on endothelial cells to inhibit angiogenesis by reducing release of blood vessel growth-signaling molecules and triggering apoptosis. In this patient, topical steroids and oral antihistamines were sufficient treatment.
Vaccine-related adverse events have been reported but remain rare. The benefits of Ad26.COV2.S vaccination for protection against COVID-19 outweigh the extremely low risk for adverse events.13 For that reason, the Centers for Disease Control and Prevention recommends a booster for individuals who are eligible to maximize protection. Intramuscular injection of Ad26.COV2.S resulted in a lower incidence of moderate to severe COVID-19 cases in all age groups vs the placebo group. Hypersensitivity adverse events were reported in 0.4% of Ad26.COV2.S-vaccinated patients vs 0.4% of patients who received a placebo; the more common reactions were nonanaphylactic.13
There have been 12 reports of cerebral venous sinus thrombosis with thrombocytopenia after Ad26.COV2.S vaccination, which sparked nationwide controversy over the safety of the Ad26.COV2.S vaccine.14 After further investigation into those reports, the US Food and Drug Administration and the Centers for Disease Control and Prevention concluded that the benefits of the Ad26.COV2.S vaccine outweigh the low risk for associated thrombosis.15
Although adverse reactions are rare, it is important that health care providers take proper safety measures before and while administering any COVID-19 vaccine. Patients should be screened for contraindications to the COVID-19 vaccine to mitigate adverse effects seen in the small percentage of patients who may need to take alternative precautions.
The broad tissue tropism and high transmissibility of SARS-CoV-2 are the main contributors to its infection having reached pandemic scale. The spike (S) protein on SARS-CoV-2 binds to ACE2, the most thoroughly studied SARS-CoV-2 receptor, which is found in a range of tissues, including arterial endothelial cells, leading to its transfection. Several studies have proposed that expression of the S protein causes endothelial dysfunction through cytokine release, activation of complement, and ultimately microvascular occlusion.16
Recent developments in the use of viral-like particles, such as vesicular stomatitis virus, may mitigate future cases of RAE that are associated with endothelial cell transfection. Vesicular stomatitis virus is a popular model virus for research applications due to its glycoprotein and matrix protein contributing to its broad tropism. Recent efforts to alter these proteins have successfully limited the broad tropism of vesicular stomatitis virus.17
The SARS-CoV-2 virus must be handled in a Biosafety Level 3 laboratory. Conversely, pseudoviruses can be handled in lower containment facilities due to their safe and efficacious nature, offering an avenue to expedite vaccine development against many viral outbreaks, including SARS-CoV-2.18
An increasing number of cutaneous manifestations have been associated with COVID-19 infection and vaccination. Eruptive pseudoangiomatosis, a rare self-limiting exanthem, has been reported in association with COVID-19 vaccination.19 Eruptive pseudoangiomatosis manifests as erythematous blanchable papules that resemble angiomas, typically in a widespread distribution. Eruptive pseudoangiomatosis has striking similarities to RAE histologically; both manifest as dilated dermal blood vessels with plump endothelial cells.
Our case is unique because of the vasculitic palpable nature of the lesions, which were localized to the left arm. Eruptive pseudoangiomatosis formation after COVID-19 infection or SARS-CoV-2 vaccination may suggest alteration of ACE2 by binding of S protein.20 Such alteration of the ACE2 pathway would lead to inflammation of angiotensin II, causing proliferation of endothelial cells in the formation of angiomalike lesions. This hypothesis suggests a paraviral eruption secondary to an immunologic reaction, not a classical virtual eruption from direct contact of the virus on blood vessels. Although EPA and RAE are harmless and self-limiting, these reports will spread awareness of the increasing number of skin manifestations related to COVID-19 and SARS-CoV-2 virus vaccination.
Acknowledgment—Thoughtful insights and comments on this manuscript were provided by Christine J. Ko, MD (New Haven, Connecticut); Christine L. Egan, MD (Glen Mills, Pennsylvania); Howard A. Bueller, MD (Delray Beach, Florida); and Juan Pablo Robles, PhD (Juriquilla, Mexico).
To the Editor:
Reactive angioendotheliomatosis (RAE) is a rare self-limited cutaneous vascular proliferation of endothelial cells within blood vessels that manifests clinically as infiltrated red-blue patches and plaques with purpura that can progress to occlude vascular lumina. The etiology of RAE is mostly idiopathic; however, the disorder typically occurs in association with a range of systemic diseases, including infection, cryoglobulinemia, leukemia, antiphospholipid syndrome, peripheral vascular disease, and arteriovenous fistula. Histopathologic examination of these lesions shows marked proliferation of endothelial cells, including occlusion of the lumen of blood vessels over wide areas.
After ruling out malignancy, treatment of RAE focuses on targeting the underlying cause or disease, if any is present; 75% of reported cases occur in association with systemic disease.1 Onset can occur at any age without predilection for sex. Reactive angioendotheliomatosis commonly manifests on the extremities but may occur on the head and neck in rare instances.2
The rarity of the condition and its poorly defined clinical characteristics make it difficult to develop a treatment plan. There are no standardized treatment guidelines for the reactive form of angiomatosis. We report a case of RAE that developed 2 weeks after vaccination with the Ad26.COV2.S vaccine (Johnson & Johnson Innovative Medicine [formerly Janssen Pharmaceutical Companies of Johnson & Johnson]) that improved following 2 weeks of treatment with a topical corticosteroid and an oral antihistamine.
A 58-year-old man presented to an outpatient dermatology clinic with pruritus and occasional paresthesia associated with a rash over the left arm of 1 month’s duration. The patient suspected that the rash may have formed secondary to the bite of oak mites on the arms and chest while he was carrying milled wood. Further inquiry into the patient’s history revealed that he received the Ad26.COV2.S vaccine 2 weeks prior to the appearance of the rash. He denied mechanical trauma. His medical history included hypercholesterolemia and a mild COVID-19 infection 8 months prior to the appearance of the rash that did not require hospitalization. He denied fever or chills during the 2 weeks following vaccination. The pruritus was minimally relieved for short periods with over-the-counter calamine lotion. The patient’s medication regimen included daily pravastatin and loratadine at the time of the initial visit. He used acetaminophen as needed for knee pain.
Physical examination revealed palpable purpura in a dermatomal distribution with nonpitting edema over the left scapula (Figure 1A), left anterolateral shoulder, left lateral volar forearm, and thenar eminence of the left hand (Figure 1B). Notably, the entire right arm, conjunctivae, tongue, lips, and bilateral fingernails were clear. Three 4-mm punch biopsies were performed at the initial presentation: 1 perilesional biopsy for direct immunofluorescence testing and 2 lesional biopsies for routine histologic evaluation. An extensive serologic workup failed to reveal abnormalities. An activated partial thromboplastin time, dilute Russell viper venom time, serum protein electrophoresis, and levels of rheumatoid factor and angiotensin-converting enzyme were within reference range. Anticardiolipin antibodies IgA, IgM, and IgG were negative. A cryoglobulin test was negative.
Histopathology revealed a proliferation of irregularly shaped vascular spaces with plump endothelium in the papillary dermis (Figure 2). Scattered leukocyte common antigen-positive lymphocytes were noted within lesions. The epidermis appeared normal, without evidence of spongiosis or alteration of the stratum corneum. Immunohistochemical studies of the perilesional skin biopsy revealed positivity for CD31 and D2-40 (Figure 3). Specimens were negative for CD20 and human herpesvirus 8. Direct immunofluorescence of the perilesional biopsy was negative.
A diagnosis of RAE was made based on clinical and histologic findings. Treatment with triamcinolone ointment 0.1% twice daily and oral cetirizine 10 mg twice daily was initiated. Re-evaluation 2 weeks later revealed notable improvement in the affected areas, including decreased edema, improvement of the purpura, and absence of pruritus. The patient noted no further spread or blister formation while the active areas were being treated with the topical steroid. The treatment regimen was modified to triamcinolone ointment 0.1% once daily, and cetirizine was discontinued. At 3-month follow-up, active areas had completely resolved (Figure 4) and triamcinolone was discontinued. To date, the patient has not had recurrence of symptoms and remains healthy.
Gottron and Nikolowski3 reported the first case of RAE in an adult patient who presented with purpuric patches secondary to skin infarction. Current definitions use the umbrella term cutaneous reactive angiomatosis to cover 3 major subtypes: reactive angioendotheliomatosis, diffuse dermal angioendotheliomatosis, and acroangiodermatitis (pseudo-Kaposi sarcoma [KS]). The manifestation of these subgroups is clinically similar, and they must be differentiated through histologic evaluation.4
Reactive angioendotheliomatosis has an unknown pathogenesis and is poorly defined clinically. The exact pathophysiology is unknown but likely is linked to vaso-occlusion and hypoxia.1 A PubMed search of articles indexed for MEDLINE, as well as a review of Science Direct, Google Scholar, and Cochrane Library, using the terms reactive angioendotheliomatosis, COVID, vaccine, Ad26.COV2.S, and RAE in any combination revealed no prior cases of RAE in association with Ad26.COV2.S vaccination.
By the late 1980s, systemic angioendotheliomatosis was segregated into 2 distinct entities: malignant and reactive.4 The differential diagnosis of malignant systemic angioendotheliomatosis includes KS and angiosarcoma; nonmalignant causes are the variants of cutaneous reactive angiomatosis. It is important to rule out KS because of its malignant and deceptive nature. It is unknown if KS originates in blood vessels or lymphatic endothelial cells; however, evidence is strongly in favor of blood vessel origin using CD31 and CD34 endothelial markers.5 CD34 positivity is more reliable than CD31 in diagnosing KS, but the absence of both markers does not offer enough evidence to rule out KS on its own.6
In our patient, histopathology revealed cells positive for CD31 and D2-40; the latter is a lymphatic endothelial cell marker that stains the endothelium of lymphatic channels but not blood vessels.7 Positive D2-40 can be indicative of KS and non-KS lesions, each with a distinct staining pattern. D2-40 staining on non-KS lesions is confined to lymphatic vessels, as it was in our patient; in contrast, spindle-shaped cells also will be stained in KS lesions.8
Another cell marker, CD20, is a B cell–specific protein that can be measured to help diagnose malignant diseases such as B-cell lymphoma and leukemia. Human herpesvirus 8 (also known as KS-associated herpesvirus) is the infectious cause of KS and traditionally has been detected using methods such as the polymerase chain reaction.9,10
Most cases of RAE are idiopathic and occur in association with systemic disease, which was not the case in our patient. We speculated that his reaction was most likely triggered by vascular transfection of endothelial cells secondary to Ad26.COV2.S vaccination. Alternatively, vaccination may have caused vascular occlusion, though the lack of cyanosis, nail changes, and route of inoculant make this less likely.
All approved COVID-19 vaccines are designed solely for intramuscular injection. In comparison to other types of tissue, muscles have superior vascularity, allowing for enhanced mobilization of compounds, which results in faster systemic circulation.11 Alternative methods of injection, including intravascular, subcutaneous, and intradermal, may lead to decreased efficacy or adverse events, or both.
Prior cases of RAE have been treated with laser therapy, topical or systemic corticosteroids, excisional removal, or topical β-blockers, such as timolol.12β-Blocking agents act on β-adrenergic receptors on endothelial cells to inhibit angiogenesis by reducing release of blood vessel growth-signaling molecules and triggering apoptosis. In this patient, topical steroids and oral antihistamines were sufficient treatment.
Vaccine-related adverse events have been reported but remain rare. The benefits of Ad26.COV2.S vaccination for protection against COVID-19 outweigh the extremely low risk for adverse events.13 For that reason, the Centers for Disease Control and Prevention recommends a booster for individuals who are eligible to maximize protection. Intramuscular injection of Ad26.COV2.S resulted in a lower incidence of moderate to severe COVID-19 cases in all age groups vs the placebo group. Hypersensitivity adverse events were reported in 0.4% of Ad26.COV2.S-vaccinated patients vs 0.4% of patients who received a placebo; the more common reactions were nonanaphylactic.13
There have been 12 reports of cerebral venous sinus thrombosis with thrombocytopenia after Ad26.COV2.S vaccination, which sparked nationwide controversy over the safety of the Ad26.COV2.S vaccine.14 After further investigation into those reports, the US Food and Drug Administration and the Centers for Disease Control and Prevention concluded that the benefits of the Ad26.COV2.S vaccine outweigh the low risk for associated thrombosis.15
Although adverse reactions are rare, it is important that health care providers take proper safety measures before and while administering any COVID-19 vaccine. Patients should be screened for contraindications to the COVID-19 vaccine to mitigate adverse effects seen in the small percentage of patients who may need to take alternative precautions.
The broad tissue tropism and high transmissibility of SARS-CoV-2 are the main contributors to its infection having reached pandemic scale. The spike (S) protein on SARS-CoV-2 binds to ACE2, the most thoroughly studied SARS-CoV-2 receptor, which is found in a range of tissues, including arterial endothelial cells, leading to its transfection. Several studies have proposed that expression of the S protein causes endothelial dysfunction through cytokine release, activation of complement, and ultimately microvascular occlusion.16
Recent developments in the use of viral-like particles, such as vesicular stomatitis virus, may mitigate future cases of RAE that are associated with endothelial cell transfection. Vesicular stomatitis virus is a popular model virus for research applications due to its glycoprotein and matrix protein contributing to its broad tropism. Recent efforts to alter these proteins have successfully limited the broad tropism of vesicular stomatitis virus.17
The SARS-CoV-2 virus must be handled in a Biosafety Level 3 laboratory. Conversely, pseudoviruses can be handled in lower containment facilities due to their safe and efficacious nature, offering an avenue to expedite vaccine development against many viral outbreaks, including SARS-CoV-2.18
An increasing number of cutaneous manifestations have been associated with COVID-19 infection and vaccination. Eruptive pseudoangiomatosis, a rare self-limiting exanthem, has been reported in association with COVID-19 vaccination.19 Eruptive pseudoangiomatosis manifests as erythematous blanchable papules that resemble angiomas, typically in a widespread distribution. Eruptive pseudoangiomatosis has striking similarities to RAE histologically; both manifest as dilated dermal blood vessels with plump endothelial cells.
Our case is unique because of the vasculitic palpable nature of the lesions, which were localized to the left arm. Eruptive pseudoangiomatosis formation after COVID-19 infection or SARS-CoV-2 vaccination may suggest alteration of ACE2 by binding of S protein.20 Such alteration of the ACE2 pathway would lead to inflammation of angiotensin II, causing proliferation of endothelial cells in the formation of angiomalike lesions. This hypothesis suggests a paraviral eruption secondary to an immunologic reaction, not a classical virtual eruption from direct contact of the virus on blood vessels. Although EPA and RAE are harmless and self-limiting, these reports will spread awareness of the increasing number of skin manifestations related to COVID-19 and SARS-CoV-2 virus vaccination.
Acknowledgment—Thoughtful insights and comments on this manuscript were provided by Christine J. Ko, MD (New Haven, Connecticut); Christine L. Egan, MD (Glen Mills, Pennsylvania); Howard A. Bueller, MD (Delray Beach, Florida); and Juan Pablo Robles, PhD (Juriquilla, Mexico).
- McMenamin ME, Fletcher CDM. Reactive angioendotheliomatosis: a study of 15 cases demonstrating a wide clinicopathologic spectrum. Am J Surg Pathol. 2002;26:686-697. doi:10.1097/00000478-200206000-00001
- Khan S, Pujani M, Jetley S, et al. Angiomatosis: a rare vascular proliferation of head and neck region. J Cutan Aesthet Surg. 2015;8:108-110. doi:10.4103/0974-2077.158448
- Gottron HA, Nikolowski W. Extrarenal Lohlein focal nephritis of the skin in endocarditis. Arch Klin Exp Dermatol. 1958;207:156-176.
- Cooper PH. Angioendotheliomatosis: two separate diseases. J Cutan Pathol. 1988;15:259. doi:10.1111/j.1600-0560.1988.tb00556.x
- Cancian L, Hansen A, Boshoff C. Cellular origin of Kaposi’s sarcoma and Kaposi’s sarcoma-associated herpesvirus-induced cell reprogramming. Trends Cell Biol. Sep 2013;23:421-32. doi:10.1016/j.tcb.2013.04.001
- Russell Jones R, Orchard G, Zelger B, et al. Immunostaining for CD31 and CD34 in Kaposi sarcoma. J Clin Pathol. 1995;48:1011-1016. doi:10.1136/jcp.48.11.1011
- Kahn HJ, Bailey D, Marks A. Monoclonal antibody D2-40, a new marker of lymphatic endothelium, reacts with Kaposi’s sarcoma and a subset of angiosarcomas. Mod Pathol. 2002;15:434-440. doi:10.1038/modpathol.3880543
- Genedy RM, Hamza AM, Abdel Latef AA, et al. Sensitivity and specificity of D2-40 in differentiating Kaposi sarcoma from its mimickers. J Egyptian Womens Dermatolog Soc. 2021;18:67-74. doi:10.4103/jewd.jewd_61_20
- Mesri EA, Cesarman E, Boshoff C. Kaposi’s sarcoma and its associated herpesvirus. Nat Rev Cancer. 2010;10:707-719. doi:10.1038/nrc2888
- Patel RM, Goldblum JR, Hsi ED. Immunohistochemical detection of human herpes virus-8 latent nuclear antigen-1 is useful in the diagnosis of Kaposi sarcoma. Mod Pathol. 2004;17:456-460. doi:10.1038/modpathol.3800061
- Zuckerman JN. The importance of injecting vaccines into muscle. Different patients need different needle sizes. BMJ. 2000;321:1237-1238. doi:10.1136/bmj.321.7271.1237
- Bhatia R, Hazarika N, Chandrasekaran D, et al. Treatment of posttraumatic reactive angioendotheliomatosis with topical timolol maleate. JAMA Dermatol. 2021;157:1002-1004. doi:10.1001/jamadermatol.2021.1770
- Sadoff J, Gray G, Vandebosch A, et al; ENSEMBLE Study Group. Safety and efficacy of single-dose Ad26.COV2.S vaccine against Covid-19. N Engl J Med. 2021;384:2187-2201. doi:10.1056/NEJMoa2101544
- See I, Su JR, Lale A, et al. US case reports of cerebral venous sinus thrombosis with thrombocytopenia after Ad26.COV2.S vaccination, March 2 to April 21, 2021. JAMA. 2021;325:2448-2456. doi:10.1001/jama.2021.7517
- Berry CT, Eliliwi M, Gallagher S, et al. Cutaneous small vessel vasculitis following single-dose Janssen Ad26.COV2.S vaccination. JAAD Case Rep. 2021;15:11-14. doi:10.1016/j.jdcr.2021.07.002
- Flaumenhaft R, Enjyoji K, Schmaier AA. Vasculopathy in COVID-19. Blood. 2022;140:222-235. doi:10.1182/blood.2021012250
- Hastie E, Cataldi M, Marriott I, et al. Understanding and altering cell tropism of vesicular stomatitis virus. Virus Res. 2013;176:16-32. doi:10.1016/j.virusres.2013.06.003
- Xiong H-L, Wu Y-T, Cao J-L, et al. Robust neutralization assay based on SARS-CoV-2 S-protein-bearing vesicular stomatitis virus (VSV) pseudovirus and ACE2-overexpressing BHK21 cells. Emerg Microbes Infect. 2020;9:2105-2113. doi:10.1080/22221751.2020.1815589
- Mohta A, Jain SK, Mehta RD, et al. Development of eruptive pseudoangiomatosis following COVID-19 immunization – apropos of 5 cases. J Eur Acad Dermatol Venereol. 2021;35:e722-e725. doi:10.1111/jdv.17499
- Angeli F, Spanevello A, Reboldi G, et al. SARS-CoV-2 vaccines: lights and shadows. Eur J Intern Med. 2021;88:1-8. doi:10.1016/j.ejim.2021.04.019
- McMenamin ME, Fletcher CDM. Reactive angioendotheliomatosis: a study of 15 cases demonstrating a wide clinicopathologic spectrum. Am J Surg Pathol. 2002;26:686-697. doi:10.1097/00000478-200206000-00001
- Khan S, Pujani M, Jetley S, et al. Angiomatosis: a rare vascular proliferation of head and neck region. J Cutan Aesthet Surg. 2015;8:108-110. doi:10.4103/0974-2077.158448
- Gottron HA, Nikolowski W. Extrarenal Lohlein focal nephritis of the skin in endocarditis. Arch Klin Exp Dermatol. 1958;207:156-176.
- Cooper PH. Angioendotheliomatosis: two separate diseases. J Cutan Pathol. 1988;15:259. doi:10.1111/j.1600-0560.1988.tb00556.x
- Cancian L, Hansen A, Boshoff C. Cellular origin of Kaposi’s sarcoma and Kaposi’s sarcoma-associated herpesvirus-induced cell reprogramming. Trends Cell Biol. Sep 2013;23:421-32. doi:10.1016/j.tcb.2013.04.001
- Russell Jones R, Orchard G, Zelger B, et al. Immunostaining for CD31 and CD34 in Kaposi sarcoma. J Clin Pathol. 1995;48:1011-1016. doi:10.1136/jcp.48.11.1011
- Kahn HJ, Bailey D, Marks A. Monoclonal antibody D2-40, a new marker of lymphatic endothelium, reacts with Kaposi’s sarcoma and a subset of angiosarcomas. Mod Pathol. 2002;15:434-440. doi:10.1038/modpathol.3880543
- Genedy RM, Hamza AM, Abdel Latef AA, et al. Sensitivity and specificity of D2-40 in differentiating Kaposi sarcoma from its mimickers. J Egyptian Womens Dermatolog Soc. 2021;18:67-74. doi:10.4103/jewd.jewd_61_20
- Mesri EA, Cesarman E, Boshoff C. Kaposi’s sarcoma and its associated herpesvirus. Nat Rev Cancer. 2010;10:707-719. doi:10.1038/nrc2888
- Patel RM, Goldblum JR, Hsi ED. Immunohistochemical detection of human herpes virus-8 latent nuclear antigen-1 is useful in the diagnosis of Kaposi sarcoma. Mod Pathol. 2004;17:456-460. doi:10.1038/modpathol.3800061
- Zuckerman JN. The importance of injecting vaccines into muscle. Different patients need different needle sizes. BMJ. 2000;321:1237-1238. doi:10.1136/bmj.321.7271.1237
- Bhatia R, Hazarika N, Chandrasekaran D, et al. Treatment of posttraumatic reactive angioendotheliomatosis with topical timolol maleate. JAMA Dermatol. 2021;157:1002-1004. doi:10.1001/jamadermatol.2021.1770
- Sadoff J, Gray G, Vandebosch A, et al; ENSEMBLE Study Group. Safety and efficacy of single-dose Ad26.COV2.S vaccine against Covid-19. N Engl J Med. 2021;384:2187-2201. doi:10.1056/NEJMoa2101544
- See I, Su JR, Lale A, et al. US case reports of cerebral venous sinus thrombosis with thrombocytopenia after Ad26.COV2.S vaccination, March 2 to April 21, 2021. JAMA. 2021;325:2448-2456. doi:10.1001/jama.2021.7517
- Berry CT, Eliliwi M, Gallagher S, et al. Cutaneous small vessel vasculitis following single-dose Janssen Ad26.COV2.S vaccination. JAAD Case Rep. 2021;15:11-14. doi:10.1016/j.jdcr.2021.07.002
- Flaumenhaft R, Enjyoji K, Schmaier AA. Vasculopathy in COVID-19. Blood. 2022;140:222-235. doi:10.1182/blood.2021012250
- Hastie E, Cataldi M, Marriott I, et al. Understanding and altering cell tropism of vesicular stomatitis virus. Virus Res. 2013;176:16-32. doi:10.1016/j.virusres.2013.06.003
- Xiong H-L, Wu Y-T, Cao J-L, et al. Robust neutralization assay based on SARS-CoV-2 S-protein-bearing vesicular stomatitis virus (VSV) pseudovirus and ACE2-overexpressing BHK21 cells. Emerg Microbes Infect. 2020;9:2105-2113. doi:10.1080/22221751.2020.1815589
- Mohta A, Jain SK, Mehta RD, et al. Development of eruptive pseudoangiomatosis following COVID-19 immunization – apropos of 5 cases. J Eur Acad Dermatol Venereol. 2021;35:e722-e725. doi:10.1111/jdv.17499
- Angeli F, Spanevello A, Reboldi G, et al. SARS-CoV-2 vaccines: lights and shadows. Eur J Intern Med. 2021;88:1-8. doi:10.1016/j.ejim.2021.04.019
Practice points
- Reactive angioendotheliomatosis (RAE) is a rare benign vascular proliferation of endothelial cells lining blood vessels that clinically appears similar to Kaposi sarcoma and must be differentiated by microscopic evaluation.
- An increasing number of reports link SARS-CoV-2 viral infection or vaccination against this virus with various cutaneous manifestations. Our case offers a link between RAE and Ad26.COV2.S vaccination.
